| Title of Invention | "POLYALKYLENE GLYCOL POLYMER COMPOUND AND USES THEREOF" |
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| Abstract | The biological activity of biologically active compounds and reduction of toxicity is addressed by the conjugation of a biologically active compound with an activated polyalkylene glycol having a moiety which covalently bonds to the compound. A pharmaceutical composition containing the polyalkylene glycol conjugate and a carrier, and a method of treating a patient by the administration of a composition with the polyalkylene glycol conjugate are described. |
| Full Text | POLYALKYLENE GLYCOL POLYMER COMPOUND AND USES THEREOF FIELD OF THE INVENTION The invention relates to novel polyalkylene glycol compounds, conjugates of the polymers and proteins, and uses thereof BACKGROUND OF THE INVENTION Covalent attachment of hydrophilic polymers, such as polyalkylene glycol polymers, also known as polyalkylene oxides, to biologically-active molecules and surfaces is of interest in biotechnology and medicine In particular, much research has focused on the use of poly (ethylene glycol) (PEG), also known as or poly (ethylene oxide) (PEO), conjugates to enhance solubility and stability and to prolong the blood circulation half-life of molecules In its most common form, PEG is a linear polymer terminated at each end with hydroxyl groups (Formula Removed) The above polymer alpha- omega-dihydroxylpoly (ethylene glycol), can also be represented as HO-PEG-OH where it is understood that the-PEG-symbol represents the following structural unit (Formula Removed) where n typically ranges from about 4 to about 10, 000 PEG is commonly used as methoxy- PEG-OH, or MPEG, in which one terminus is the relatively inert methoxy group, while the other terminus is a hydroxyl group that is subject to ready chemical modification Additionally, random or block copolymers of different alkylene oxides (e g , ethylene oxide and propylene oxide) that are closely related to PEG in their chemistry can be substituted for PEG in many of its applications To couple PEG to a molecule of interest, it is often necessary to activate the PEG by preparing a derivative of the PEG having a reactive functional group at least at one terminus The functional group is chosen based on the type of available reactive group on the molecule that will be coupled to the PEG PEG is a polymer having the properties of solubility in water and in many organic solvents, lack of toxicity, and lack of immunogenicity One use of PEG is to covalently attach the polymer to insoluble molecules to make the resulting PEG-molecule conjugate" soluble For example, it has been shown that the water-insoluble drug paclitaxel, when coupled to PEG, becomes water-soluble. Greenwald, et a!, J Org Ckem., 60 331-336 (1995)i The prodrug approach, m which drugs are released by degradation of more complex molecules (prodrugs) under physiological conditions, is a powerful component of drug delivery. Prodrugs can, for example, be formed by bonding PEG to drugs via linkages which are degradable under physiological conditions The lifetime of PEG prodrugs in vivo depends upon the type of functional group(s) forming linkages between PEG and the drug In general, ester linkages, formed by reaction of PEG carboxylic acids or activated PEG carboxyhc acids with alcohol groups on the drug hydrolyze under physiological conditions to release the drug, while amide and carbamaie linkages, formed from amine groups on the drug, are stable and do not hydrolyze to release the free drug It has been shown that hydrolytic delivery of drugs from PEG estets can be favorably controlled to a certain extent by controlling the number of linking methylene groups in a spacer between the terminal PEG oxygen and the carbonyl group of the attached carboxyhc acid or carboxylic acid derivative For example, Hams et ah, in U S. Patent No 5,672,662, describe PEG butanoic acid and PEG propanoic acid, and activated denvatives thereof, as alternate es to caiboxymethyl PEG for compounds where less hydrolytic reactivity in the corresponding ester derivatives is desirable See, generally, PCT publication WO 01/46291 One factor limiting the usefulness of proteinaceous substances for medical treatment applications is that, when given parenterally, they are eliminated from the body within a short time This elimination can occur as a result of degradation by proteases or by clearance using normal pathways for protein elimination such as by filtration in the kidneys Oral administration of these substances is even more problematic because, in addition to proteolysis m the stomach, the high acidity of the stomach destroys these substances before they reach their intended target tissue The problems associated with these routes ot administration of proteins are well known in the pharmaceutical industry, and vanous strategies are being employed in attempts to solve them A great deal of work dealing with protein stabilization has been published Vanous ways of conjugating proteins with polymeric materials are known, including use of dextrans, polyvinyl pyrrohdones, glycopeptides, polyethylene glycol, and polyamino acids The resulting conjugated polypeptides are reported to retain their biological activities and solubility in water for parenteral applications. Of particular interest is increasing the biological activity of interferons while reducing the toxicity involved with use of these proteins for treating human patients Interferons are a family of naturally-occurring small proteins and glycoproteins produced and secreted by most nucleated cells in response to wral infection as well as to other antigenic stimuli. Interferons render cells resistant to viral infection and exhibit a wide variety of actions on cells They exert their cellular activities by binding to specific membrane receptors on the cell surface Once bound to the cell membrane, interferons initiate a complex sequence of intracellular events. In vitro studies have demonstrated that these include the induction of certain enzymes; suppression of cell proliferation, immunomodulation activities such as enhancement of the phagocytic activity of macrophages; augmentation of the specific cytotoxicity of lymphocytes for target cells; and inhibition of virus replication in virus-infected cells Interferons have been tested in the treatment of a variety of clinical disease states The use of human interferon beta has been established in the treatment of multiple sclerosis Two forms of recombinant interferon beta, have recently been licensed m Europe and the U S for treatment of this disease interferon-beta-la (AVONEX ®, Biogen, Inc , Cambridge, MA and REBIF * Serono, Geneva, Switzerland) and interferon-beta-lb (BETASERON*, Berlex, Richmond. CA). Interferon beta-la is produced in mammalian cells using the natural human gene sequence and is glycosylated, whereas interferon beta-lb is produced in E coli bacteria using a modified human gene sequence that contains a genetically engineered cysteine-to-serine substitution at ammo acid position 17 and is non-giycosylated. Non-immune interferons, which include both alpha and beta interferons, are known to suppress human immunodeficiency virus (HIV) m both acutely and chronically-infected ceils. See Poli and Fauci. 1992, AIDS Research and Human Retroviruses 8(2). 191-197. Due to their antmral activity, interferons, in particular alpha interferons, have received considerable attention as therapeutic agents in the treatment of hepatitis C virus (HCWrelated disease See Hoofnagle ctal, in. Viral Hepatitis 1981 International Symposium, 1982, Philadelphia, Franklin Institute Press, Hoofnagle et al., 1986, New hng. J Med 315.1575-1578, Thomson, 1987, Lancet L539-541 Kiyosawa et al, 1983. nr Zuckerman, ed , Viral Hepatitis and Liver Disease, Allen K. Liss, New York pp 895-897, Hoofnagle etal., 1985, Sem LivDis,1985, 9 259-263 Interferon-polymer conjugates are described m. for example, U.S. Pat. No. 4,766,106, US Pat No 4,917,888, European Patent Application No. 0 236 987, European Patent Application No. 0 510 356 and International Application Publication No WO 95/13090 Chronic hepatitis C is an insidious and slowly progressive disease having a significant impact on the quality ot life Despite improvement in the quality of the blood-donor pool and the recent implementation of testmg of donated blood for HCV, the estimated incidence of acute infection among persons receiving transfusions is 5 to 10% See Alter ct al, m" Zuckerman, ed,, Viral Hepatitis and Liver Disease, Allen K Liss, New York. 1088, pp 537-542. Thus, of the approximately 3 million persons who receive transfusions, m the United States each year, acute hepatitis C will develop m about 150.000. While many patients who contract hepabtis C will have subclinical or mild disease, approximately 50% will progress to a chrome disease state characterized by fluctuating scrum transaminase abnormalities and inflammatory lesions on liver biopsy It is estimated that cirrhosis will develop in up to about 20% of this group. See Koretz et al, 1985, Gastroenterology 88 1251-1254 Interferons are known to affect a variety of cellular functions, including DNA replication, and RNA and protein synthesis, in both normal and abnormal cells Thus, cytotoxic effects of interferon are not restricted to tumor or virus-mfectod cells but are also manifested in normal, healthy cells As a result, undesirable side effects may arise during mterferon therapy, particularly v\hen high doses are required Administration of interferon can lead to myelosuppression, thereby resulting in reduced ted blood cell count, and reduced white blood cell and platelet levels. Interferons commonly give rise to flu-like symptoms (eg, fever, fatigue, headaches and chills), gastrointestinal disorders (e g, anorexia, nausea and diarrhea), dizziness and coughing. Often, the sustained response of HCV patients to non-PEGylated interferon treatment is low and the treatment can induce severe side effects, including, but not limited to, retinopathy, thyroiditis, acute pancreatitis, and depression The undesirable side effects that accompany mterferon therapy frequently limit the therapeutic usefulness of mterferon treatment regimes. Thus, a need exists to maintain or improve me therapeutic benefits of such therapy while reducing or eliminating the undesirable side effects. SUMMARY OF THE INVENTION The invention relates to novel polyalkylene glycol compounds, conjugates of tliehe compounds, and uses thereof In one aspect, the invention relates to an activated polyalkylene glycol polymer having the structure according to Formula I (Formula Removed) wherein Pisa polyalkylene glycol polymer, X and Y are independently 0, S, CO, CO2, COS, SO, SO:, CONR'. SO2NR\ or NR'; 0 ts a C3 to C8 saturated or unsaturated cyclic aJkyl or cyclic heteroalkyl (including fused bicychc and bndged bicychc ring structures), a substituted or unsubstituted aryl or heteroaryl group, or a substituted or unsubstituted alkaryl wherein the alkyl is a Q to Czo saturated or unsaturated alkyl or heteroalkaryl group, wherein the subshtucnts are seise ted from the group consisting of bdlogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl. phosphoryl, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, mtro, azido, sulfliydryl, sulfate, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, lmuio, sulfamoyl, sulfonate, silyl, ether, and alkylthio; each R'. Z and Z' is independently hydrogen, a straight- orbranched-cham, saturated or unsaturated C1 to C20 alk>rl or heteroalkyl group, C1 to Cs saturated or unsaturated tyclic alkyl or cyclic heteroalkyl, a substituted or unsubstitutcd aryl or heteroaryl group 01 a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C2n saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate. thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, mtro, azido, sulfliydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, sulfamoyl, sulfonate, silyl, ether, and alkylthio; R is a moiety suitable for forming a bond between the compound of Formula 1 and a biologically-active compound or precursor thereof, m is 0 or 1, each n 13 independently 0 or an integer from 1 to 5, and pis 1,2, or 3 In another aspect, the invention relates to an activated polyalkylcnc glycol compound (PGCl having the structure according to Formula la. (Formula Removed) where P is a polyalkylene glycol polymer, m is zero or one. n is zero or an integer from one to five, and X and Y are independently 0. S, CO, CO?) COS, SO, SO2, CONR'. SO2NR\ or NR' 0 is a C1 to Q saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group, or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group If present, the substituents can be halogen, hydroxyl, carbonyl, caiboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphmate, amino, amido, amidine, vmine, cyano, nitro, azido. sulfhydryl, sulfate, sulfonamide, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaroniatic moiety, rmino, sulfamoyl, sulfonate, silyl, ether, or alkylthio Heterocyclic and carbocychc groups include fused bicyclic and bridged bicyclic ring structures Each R'and Z is independently hydrogen, a straight- or branched-chain, saturated or unsaturated C1 to C10 alkyl or heteroalkyl group, C3 to C8 saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted ur unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group. The substituents can be halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioestcr, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidme, inline, cyano, nitro, azido. sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, lmino, silyl, ether, or alkylthio Compounds which include chiral carbons can be m the R configuration, the S configuration, or may be raccmic R is a moiety suitable for forming a bond between the compound of Formula I aud a biologically-active compound or precursor thereof. In one embodiment, R is a carboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkeny], acrylate, niethacrylate, acrylamide, substituted 01 unsubstituted thiol, halogen, substituted orunsubstituted amine, protected amine, hydraztde, protected hydrazide, succimmidyl, isocyanate, isothiocyanate, dithiop)Tidine, vmylpyndine, lodoacetamide, epoxide, hydroxysuccmimidyl, azole, maleimide, sulfone. allyl, vfnylsulfone, tresyl, sulfo-N-succimmidyl, dione, mesyl, tosyl, or a glyoxal moiety In certain embodiments, P is a polyethylene glycol having the structure of Formula II: (Formula Removed) where E is hydrogen or a straight- or branched-chain C1 to C20 alkyl group and a is an integer from 4 to 10,000 For e.viniple. E can be a methyl group In other embodiments, E can be a detectable label, such as, for example, a radioactive isotope, a fluorescent moiety, a phosphorescent moiety, a chemihimineseent moiety, or a quantum dot. In yet other embodiments, E is a moiety suitable for forming a bond between the compound of Formula 1 and a biologically-active compound or precursor thereof. For example, E can be a carboxyhc acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkcnyl. acryiate, mcthacrylate, acrylamidc, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succimmidyl, isocyanate, isothiocyanate, dithiopyndme, vmylpyndine, lodoacetamide, epoxide, hydroxysuccinimidyl, azoic, maieimide, sulfone, allyl, vinylsulfone, tresyl, sulfo-N-succinrmidyl, dione, mesyl, tosyl, or a glyoxal moiety In still other embodiments, E has the structure according to Formula III or Formula IV: (Formula Removed) where each Q, X, Y, Z, m, and n are, independently, as defined above, and each W is, independently, hydrogen 01 a C1 to C7 alkyl R"isa moiety suitable for forming a bond between the compound of Formula in and a biologically-active compound or precursor thereof, and R'" is a moiety suitable for forming a "bond between the compound of Formula IV and a biologically-active compound or precursor thereof. For example, R1' and R"' can be a carboxyhc acid, ester, aldehyde, aldehyde hyoVate. acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succurimidy), isocyanate, isothiocyanate, dithiopyndme, vinylpyndine, iodoacetamide, epoxide, hydxoxysuccinimidyl, a^ole, maieimide. sulfone, allyl, vmylsulfone, tresyl, sulfo~N-8iiccimmidyl, dione, mesyl, tosyl, or a glyoxal moiety R" and R""1 can be the same or different from R. In particular embodiments, Q is a substituted or unsubstituted aUcaryi. In another aspect, the invention relates to an activatedPGC having the structure according to Formula V- (Formula Removed) where P, X \, R', Z, R, m, and n are as defined, and Ti and T} are, independently, absent, or a straight- or branched-chain, saturated or unsaturated d to Qo aikyl or heteroalkyl group, a C1 to C» saturated or unsaturated eye hi dlkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group, or a substituted or unsubstituted alkaryl wherein the aikyl is a C1 to C'asaturated or unsaturated aikyl or heteroalkaryl group The substituents can be halogen, hydroxy), carhonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonatc, phosphmatc, ammo, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl. sulfonamide, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heieroaromahc moiety, immo, sJy], ether, oralkylthio. L may be absent (e.g., d is zero) or there may be from one to four (e.g., n is an integer from one to four) L substituents on the aromatic nng in addition to the 'l\ and Tj substituents, and each L is, independently, a straight- or branched-chaw, saturated or unsaturated C1 to C2o aikyl or heteroalkyl group, C} to C8 saturated or unsaturated cyclic aikyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the aikyl is a G to £■$ R is a moiety suitable for forrntng a bond between the compound of Formula V and a biologically-active compound or precursor thereof. For example. R is chosen from earboxyiic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, actyLimide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, bydrazide, protected hydrazide, succmimidyl, isocyanate, isothiocyanatc, drthiopyndine, vmylpyridine, lodoacetamide, epoxide, hydroxysuccmimidyl, azole, maleimide, sulfone, allyl vinylsulfone, tresyl, suIfo-N-succinimidyl, dione, mesyl, tosyl and glyoxal In one embodiment of the activated polyalkylene glycol polymer of formula V, P is a polyethylene glycol having the structure of Formula II (Formula Removed) where E is hydrogen or a straight- or branched-chain C1 to C20 alky] group and a is an integer from 4 to 10.000 For example, E can be methyl In other embodiments, E is a detectable label, such as, for example, a radioactive isotope, fluorescent moiety, phosphorescent moiety, chemi luminescent moiety, or a quantum dot. In another aspect, P is a polyethylene glycol having the structure of Formula II, (Formula Removed) where E is a moiety suitable for forming a bond between the compound of Formula V and a biologic a lly-actrve compound or precursor thereof and a is an integer from 4 to 10,000 For example, E is chosen from caiboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylarnide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succmrrmdyl, isocyanate, isothiocyanate, dithiopyndme, vinylpyndine, lodoacetarmde, epoxide, hydrnxysuccmrnndyl, azole, maleimide, sulfone, ally], vinylsulfone, tresyl, sulfo-N-succmimidyl, dione, mesyl, tosyl, arid glyoxal moieties. In another aspect, E lias the structure according to formula HI or Formula IV (Formula Removed) Z where 0 is a C3 to C8 saturated or unsaturated cyclic alkyl or cyclic heteroalkyl (including fused bicychc and bridged bicyclic nng structures), a substituted or unsubstituted aryl or hcteroaryl group or a substituted or unsubstituted arkaryl, the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, and the substituents can be of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioaceuite, thioformate, alkoxyl, phosphoryl, phosphonale, phosphmatc, amino, armdo. amidine. inline, cyano, nitro. azido, sulfliydryi, sulfate, suifonate, sulfamoyl, suifonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, lmko, silyl, ether, or alkylthio. X, Y, Z, m, and n are as defined, and each W is, independently, hydrogen or a C1 to C7 alkyl; and R" is a moiety suitable for forming a bond between the compound of Formula III and a biologically-active compound or precursor thereof, and R'" is a moiety suitable for forming a bond between die compound of Formula IV and a biologically-active compound or precursor thereof In certain embodiments, R" and R'" can be the same as or different from R, and are chosen from carboxylic acid, ester, aldehyde, aldehyde hydrate, acctal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacryjate, acrylamidc, substituted or unsubstitutcd thiol, halogen, substituted or unsubstitutcd amine, protected amine, hydrazide, protected liydrazide, succinimidyl, isocyanatc, isothiocyanatc, dithiopyridinc, vinyJpyridine, lodoacetamide, epoxide, hydroxysuccmimidyl, azoic, malcimidc, sulfone, allyl, vinylsulfbnc, tresyi, sulfo-N-succtninudyl, dione, mesyl, tosyl, and glyoxal moieties In one embodiment of the compound of Formula V, X and Y, if present, are oxygen In another aspect the invention relates to an activated PGC having the structure according to Formula VI (Formula Removed) where F is a polyalkyiene glycol polymer, m is zero or one, n is zero or an integer from one to five, X and Y are independently 0, S, CO, CO2, COS, SO, SO:, CONR'. SOjNR', or NR', and T1 and T2 are, independently, absent, or a straight- or branched-chain, saturated or unsaturated C1 to C^ alkyl or hctcroalkyl group Each R' and Z is, independently, hydrogen, a straight- or branched-chain, saturated or unsaturated C1 to C20 alkyl or heteroalkyl group d is zero or an integer from one to four; and each L is. independently, a straight- or branched-chain. saturated or unsaturated C1 to C20 alkyl or hctcroalkyl group, C3 to C8 saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstiruted aryl or heteroaryl group or a substituted or unsubstitutcd alkaryl wherein the alkyl is a C3 to C20 saturated or unsaturated alkyl or hcteroalkaryl group The suhstituents are selected from halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyi, thiocarbonyl, thioester. thioacetate, Ihioformate. alkoxyl, phosphOTyl, phosphoiuite, phosphinate, amino, amido, amidme, imme, cyano, nitro, azido, sulfhydiyl, sulfate, sulfonate, sulfamoy], sulfonamide, sulfonyl. heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, or alkylthio moieties In one embodiment, the activated PGC according to Formula VI has the structure according to Formula VII or formula VIII' (Formula Removed) In one embodiment of the activated polyalkylene glycol compounds of Formulae VII and VTJI, P is a polyethylene glycol having the structure of Formula IF (Formula Removed) where E is hydrogen or a straight- or branched-cham C,\ to C20 alkyl group and a 13 an integer from 4 to 10,000 For example, F can be methyl In other embodiments, E is a detectable label, such as, for example, a radioactive isotope, fluorescent moiety, phosphorescent moiety, chemilumuiescent moiety, or a quantum dot b another aspect, P is a polyethylene glycol having the structure of Formula II' (Formula Removed) where h is a moiety suitable for forming a bond between die compound of Formula VII or VIII and a biologically-active compound or precursor thereof and a is an integer from 4 to 10,000 For example, E is chosen from carboxyhc acid, ester, aldehyde, aldehyde hydrate, acetal. hydroxy, protected hydroxy, carbonate, alkerry], acrylate. mcthacrylate, acrylamide. substituted ornnsubstinited thiol, halogen, substituted or un substituted amine, protected amine, hydrazide, protected hydrazide. sucunmudyl, isocyanatc, isothiocyanate, dithiopyndfoe, vmylpyndme, lodoacetamide, epoxide, bydroxysuccinimidyl, azole, maleimide. sulfone, allyl, vmyl^ulfone, tresyl, sulfo-N-succimmidvl, dione. mesyl, tosyl, and glyoxal moieties In another aspect, E has the structure according to Formula III or Formula IV: (Formula Removed) where Q is a C3 to C% saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group, or a substituted or unsubstitutcd alkaryl, the aikyl is a C1 to C20 saturated or unsaturated alkyl or heleroalkaryl group, and the subsiiluents can be of halogen, hydroxy], carbonyl, carboxylate, ester, fcrniyl, acyl, thiocarbonyl, (hioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, ammo, amido, armdine, imine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyt, heterocyclyl, aralkyi, aromatic moiety, hetcroaromatic moiety, rmino. silyl, ether, or alkvlUhio. Heterocyclic and carbocyclic groups include fused bicyclic and bridged bicychc ring structures X, Y, Z, m, and n are as defined, and each W is, independently, hydrogen or a C1 to C7 alkyl; and R" is a moiety suitable for forming a bond between the compound of Formula III and a biologically-active compound or precursoi thereof, and R,!' is a moiety suitable for forming a bond between the compound of Formula IV and a biologically-active compound or precursor thereof. In certain embodiments, R." and R'" can be the same as or different from R, and are chosen from carboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, piotected hydroxy, carbonate, alkenyl, aery late, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazidc, suceinmndyl, isocyanate, isothiocyaruite. dithiopyridine, vmylpyndinc, iodoacetamide, epoxide, hydroxysuccinimidyl, a^ole, maleimide, sulfone, ally], vinylsulfone, tresyl, sulfo-N-succinimidyl, dione, mesyl, tosyl, and glyoxal moieties. Li one embodiment, the activated polyalkylene glycol compound of Formula Vffl, the ring substitucnts are located m a meta arrangement. In another embodiment, the ring substituents are located in a para arrangement In another embodiment, the activated polyalkylene glycol compound according to Formula VI, has the structure according to Formula IX (Formula Removed) wherc Pisa polyalkylene glycol polymer, each n and u are, independently, zero or an integer from one to five; and Z is hydrogen, a straight- 01 branched-chain, saturated or unsaturated C( to C20 alkyl or heteroalkyl group In one embodiment of the compounds of Formula IX, the ring substituents are located in a meta arrangement In another embodiment of the compounds of Formula IX, the ring substituents are located in a para arrangement In another embodiment of the compounds of Formula IX, P is a polyethylene glycol having the structure of Formula II (Formula Removed) where B is hydrogen, a straight- or branchcd-chain C1 to C20 alkyl group, a detectable label, or a moiety suitable for forming a bond between the compound of Formula IX and a biologically-active compound or precursor thereof and a is an integer from 4 to 10,000. In another aspect, the invention involves an activated polyalkylene glycol polymer having the structure according lo Formula X (Formula Removed) wherein P is a pofyalkylene glycol polymer. X is 0, S, CO. CO2, COS, SO, SO2, CONR'. SO2NR\ or NR'; R" is hydrogen, a straight- or branched-cham, saturated or unsaturated C'I to C'20 alkyl or heteroalkyl group, C1 to C? saturated onmsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or umubstiruted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxy], carbonyl, carboxylate, ester, furmyl, acyl, thiocarbonyl, thioester, thioacetate, tbioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonanndo, sulfonyl. heterocyclyl, aralkyl, aromatic moiety, lieteroaromatic moiety, immo, silyl, ether, and alkylthio, Z and Z' are individually hydrogen, a straight- or branched-cham, saturated or unsaturated C1 to C20 alkyl or heteroalkyl group, C1 to Ca saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the substibients are selected from the group consisting of halogen, hydioxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidine. imine, cyano, rntro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonanrido. sulfonyl, heterocyclyl, aralkyl, aromatic moiety, hetcroarotnatic moiety, imino, silyl, ether, and alkylthio, provided that at least one Z or Z' is not hydrogen; R is a moiety suitable for forming a bond between the compound of Formula X and a biologically-active compound or precursor thereof; each n is independently 0 or an integer from 1 to 5; and pis 1,2, or 3 In another aspeU, the invention involves an activated polyalkylene glycol compound (PGC) having the structure according to Formula Xa. (Formula Removed) In these compounds, P is a polyalkylene glycol polymer, such as, for example, PEG or mPEG X is O, S, CO, CO2, COS, SO, SO.., CONR\ SO2NR'. or NR', and R\ if present, is hydrogen, a straight- or branched-chain, saturated or unsaturated C\ to C20 alkyl or heteroalkyl group. C3 to Cs saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate. ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, anudo, amidine, imine, cyano, nitro, azido, sulfliydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyL heterocyclyl, aralkyl, aromatic moiety, hetaroaromatic moiety, immo, sily], ether, ami alkylthio Z is a straight- or bianched-cham, saturated or unsaturated C1 to C30 alkyl or heteroalkyl gioup, C3 to C8 saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to Go saturated or unsaturated alkyl orheteroalkaryl group, wherein the subshtuents are selected from the group consisting of halogen, hydroxyl, carbon) I, carboxylate ester, fomvyl, acyl, thiocarbonyl, thtoester, thioacetate. thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidme, rmme, cyano, nitro, azido, sulfliydryl. sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety- hetcroaromatic moiety, muno, silyl. ether, and alkylthio R is a moiety suitable for forming a bond between the compound of Formula X and a biologically-active compound or precursor thereof; and n is 0 or an integer from 1 to 5, such that there are between zero and live methylene groups between X and the Z-containing carbon In one embodiment, R is chosen from the group consisting of carboxyhc acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkerryl, acrylate, mefhacrylate, acryiamide, substituted or unsubstituted thiol, halogen, substituted 01 unsubstituted amine, protected amine, hydrazide, protected hydrazide, succinimidyl, isocyanate, isotmocyartate, dithiopyriduie, vinylpyridine, lodoacetaimde, epoxide, hydroxysuccummdyl, azole, malcimide, sulfone, ally], vmylsulfone, tresyl, sulfo-N-succimmidyl, dione, mesy 1, tosyl, and glyoxal. In another embodiment, P is a polyethylene glycol having the structure ot Formula II: (Formula Removed) wherein E is hydrogen, a straight- or branched-chain C1 to C20 alkyl group, or a detectable label, and a is an integer from 4 to 10,000 In a further embodiment, E may be methyl. In yet another embodiment, P is a polyethylene glycol having the structure of Formula II, wherein E is a moiety suitable for forming a bond between the compound of Formula X and a biologically-active compound or precursor thereof and a is an integer from 4 to 10,000 In an additional embodiment, E is chosen from the grnup consisting of carboxyhc acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydrux>, carbonate, alkenyl, acrylate, meihaerylate, acryiamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succirumidyl, isocyanate, isothiocyanate, dithiopyridine, vinylpyndrne, lodoacetamide, epoxide, hydroxysuccinimidyl, azole, maleimide, sulfone, ally], vrnylsulfone, tresyl, sulfo-N-succinimidyl, dione, mesyl, losyl, and glyoxal Alternatively, E may have the structure according to Formula IE (Formula Removed) wherem P is a polyalkylene glycol polymer, X and Y are independently 0, S, CO, CO2, COS, SO, SO2, CONR\ SO2NR\ orNR'; Q is a C3 to Cs saturated or unsaturated cyclic a/kyl or cyclic heteroalkyl (including fused bicychc and bndged bicyclic nng structures), a substituted or unsubstituted aryl or heteroaryl group, or a substituted or unsubstituted alkaryl wherein the alkyl is a C| to C20 saturated or unsaturated alkyl or heteroalkaiyl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidme, imine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, immo, silyl, ether, and alkylthio, R' and each Z are independently as described above; m is 0 or 1, each W is, independently, hydrogen or a C'i to C7 alkyl, each n is independently 0 or an integer from 1 to 5, and R" is a moiety suitable for forming a bond between the compound of Formula III and a biologically-active compound or precursor thereof Heterocyclic and carbocyclic groups include fused bicyclic and bndged bicyclic nng structures In still a further embodiment, E has the structure according to Formula IV: (Formula Removed) Z wherein each X, Z and n are, independently, as defined, each W is, independently, hydrogen or a Q to C7 alkyl, and R!" is a moiety suitable for forming a bond between the compound of Formula IV and a biologically-active compound or precursor thereof. In an additional embodiment, R" is chosen from the group consisting of carboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succimmidyl, isocyanatc, isothiocyanate, dithiopyriJme, vmylpyndme, iodoacetamide, epoxide, hydroxysuccmimidyl, azole, malerrmde, sulfoae, allyl, vinylsulfone, tresyl, sulfo-N-succmimidyl, dione, mesyl. tosyl, and glyoxal. In a further embodiment, R'" is chosen from the group consisting of carboxylic acid, rster, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, mediacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succimmidyl, isocyanate, isothiocyanate, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, hydroxysuccmimidyl, azole, malcumde, sultone, allyl, vinylsulfone, tresyl, sulfo-N-succimmidyl, dionc, mesyl, tosyl, and glyoxal. In another embodiment, E is a detectable label. Additionally, E may be selected from the group consisting of radioactive isotopes, fluorescent moieties, phosphorescent moieties, chemilummescent moieties, and quantum dots In still another embodiment, the activated PGC according to the invention has the structure according to Formula XI: (Formula Removed) wherein P is a polyalkylene glycol polymer; and n and Z are as defined. In another embodiment, the activated polyalkylene glycol has the structure according to Formula XII • (Formula Removed) wherein n, a, arid Z are as defined above In one embodiment, Z may be methyl. In some embodiments, n is one In another aspect, the invention involves an activated polyaikylene glycol compound of having the structure according to Formula XIII (Formula Removed) where a is an integer from 4 to 10,000 The invention is also concerned with a composition of the activated polyaikylene glycol compounds ol the invention and a biologically-active compound or precursor thereof. In i anous embodiments, the biologically-active compound or precursor thereof is chosen from the group consisting of a peptide, peptide analog, protein, enzyme, small molecule, dye, lipid, nucleoside, oligonucleotide, oligonucleotide analog, sugar, oligosaccharide, cell, virus, liposome, irncroparticle, surface, and a micelle. In another aspect, the invention provides a composition having the structure according to Formula XIV (Formula Removed) wherein Pisa polyaikylene glycol polymer, Xand Ya» independently 0, S. CO, CO;, COS, SO. SQ>, CONR', SQ.NR\ DJNK\ 0 is a d to Cg saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or hcteroaryl group, or a substituted or unsubstituted alkaryl wherein the alkyl is a C, to C;o saturated or unsaturated alkyl or heteroalkaryl group, wherein the substhnems are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate. ester, formyl, acyl, thiocarborryl, thioester. thioacetate, thioformate, alltoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, salfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyi, ether, and aikylthio; each R', Z, and Z' is independently hydrogen, a straight- or branched-chain, saturated or unsaturated C| to C20 alkyl or heteroalkyl group, C1 to Cg saturated or unsaturated cyclic aikyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alfcaryl whercm the alkyl is a C| to C20 saturated or unsaturated alkyl or hctcroalkaiyl group, wherein the substituenls are selected from the group consisting of halogen, hydroxyl, carbony!, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphmate, amino, amido, amidine, hnine, cyano, rniro. azido, sulfhydryl, sulfate, sulfonate, salfamoyl, sulfonamido, sulfonyl, heterocycly!, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and aikylthio, R* is a linking moiety; B is a biologically-active compound or precursor thereof, m isOor 1, each n is independently 0 or an integer from 1 to 5, and p is 1.2. or 3. In another aspect, the invention involves a composition having the structure according lo Formula XIW (Formula Removed) wherein P is a polyalkylene glycol polymer, X and Y are independently O, S, CO, CO2, COS, SO, SOj, CONR\ SOjNR', or NR'; Q is a C1 to Cg saturated or unsaturated cyclic alkyl or cyclic heteroalkyl (including fused bicyclic and bridged bicyclic ring structures), a substituted or unsubstituted aryl or bctcroary] group (including fused bicyclic and bridged bicyclic ring structures), or a substituted or unsubstituted alkaiyl whercm the alkyl is a C1 to C'^j saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, carbonyl carboxylate, ester, lormyl, acyl, thiocarbonyl, thioester. thioacctate, thiofoimate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, mtro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, hcteroaromatic moiety, ltnino, silyl, ether, and alkylthio, each R' and Z is independently hydrogen, a straight- or branched-chain, saturated or unsaturated C\ to C20 alkyl or heteroalkyl group, C3 to Cg saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or hcteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to do saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxy], carbonyl, carboxylate, ester, formy], aeyl. thiocarbonyl, thioester, tliioacetate, thiofoimate, alkoxyl, phosphoryl, phosphonate, phosphinate, ammo, amido, amidine, imine, cyano. nitro. azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl. aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkylthio; R* is a linking moiety formed from the reaction of R with a biologically-active compound or precursor thereof; B is a biologically-active compound or precursor thereof after conjugation with R; m is 0 or 1; and n is 0 or an integer from 1 to 5. In one embodiment. R* is a linking moiety formed from the reaction o( R with a biologically-active compound or precursor thereof For example, R is a moiety selected from the group consisting of carboxyhc acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succinimidyl, isocyanatc, isothiocyanate, dithiopyridine, vmylpyndme, iodoacetamide, epoxide, hydroxysuccimmidyl, azole, maleimide, sulfone, ally], vmylsulfone, tresyl, sulfoN-succimmidyl, dione, mesyl, tosyl, and glyoxal In another embodiment, P is a poly ethylene glycol having the structure of Formula II- (Formula Removed) wherein E is hydrogen, a straight- or branched-chain t "1 to C20 alkyl group, or a detectable label, and a is an integer from A to 10,000. In this embodiment, E may be methyl. In a further embodiment, ? is a polyethylene glyuol having the structure of Formula II- (Formula Removed) wherein E13 a moiety suitable for forming a bond between the compound of Formula XIV and a biologically-active compound or precursor thereof and a is an integer from 4 to 10,000 Here, in still a further embodiment, E may form a bond to another biologically-active compound, B Alternatively, E may form a bond to a biologically-active compound other than B. E may also form an additional bond to the biologically-active compound, B In \anous embodiments, E may be chosen from the group consisting of carboxyhc acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamide, substituted or vrasubsti Luted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succinimidyl, isocyanate, isothiocyanatc, dithiopyndine, vinylpyndme, lodoacetamide, epoxide, hydroxy succinimidyl, azole, maleimide. sulfone, allyl, vrnylsulfone, tresyl, .sulfo-N-succinimidy], dione, mesyl, tosyl, and glyoxal In another embodiment. E may have the structure according to Formula III (Formula Removed) wherein each Q, X, Y Z, m, and n are, independently, as defined, each W is, independently, hydrogen or a C1 to C? alky], and R" is a moiety suitable for forming a bond between the compound of Formula HI and a biologically-active compound or precursor thereof In a further embodiment, E has the structure according to Formula IV- (Formula Removed) wherein each X. Z and n are, independently, as defined, each W is, independently, hydrogen or a C, to C7 alkyl, and R ' is a moiety suitable for forming a bond between the compound of Formula IV and a biologically-active compound or precursor thereof In various embodiments, K" is chosen from the group consisting of carboxyhc acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylaiiude, substituted or unsubstituted thiol, halogen, substituted or unsubstitiited amine, protected amine, hydrazide, protected hydrazide, succmimidyl, isocyanate. lsothiocyanate, dithiopyridme, vinylpyridme, iodoacetamide, epoxide, hydroxysuccmimidyl. azole, maleimide, sulfone, allyl, vmylsulfone, tresyl, sulfo-N-succinimidyl, dione, mesyl, tosyl, and glyoxal Likewise, in other embodiments, R"" is chosen from the group consisting of carboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate. acrylanude, substituted or unsubstitiited thiol, halogen, substituted or unsubstvruted amine, protected amine, hydrazidc, protected hydrazide, succmimidyl, isocyanate. lsothiocyanate, dithiopyndmc, vinylpyridme, iodoacetamide, epoxide, hydTOKysuccinimidy], azole, maleimide. sulfone. allyl, vmylsulfone, tresyl, siilfo-N-succimmidyl, dione, mesyl, tosyl, and glyoxal. In still other embodiments, E is a detectable label For example, E may be selected from the group consisting of radioactive isotopes, fluorescent moieties, phosphorescent moieties, Lhenuluminescent moieties, and quantum dots In various embodiments, Q is a substituted or unsubstituted alkaryl In another aspect, the invention involves a composition having the structure according to Formula XV: (Formula Removed) wherein P is a polyalkylene gfycol polymer, m is zero or one, d is zero or an integer from one to four, and n is zero or an integer from one to five X and Y are independently O, S, CO, CO?, COS. SO, SO3, CONR', SO2NR', orNR'; and T1 and T2 are, independently, absent, or a straight- 01 branched-chain, saturated or unsaturated C1 to C20 alkyl or heteroalkyl group, a C3 to Cs saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group, or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or hetcroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, caibonyl, carboxylate, ester, formyl, acyl. thiocarbonyl, thioester, thioacetate, thiofonnate, alkoxyl, phosphoryl, phosphorate, phosphmate, amino, anndo, amidrne, inline, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamide sulfonyl, heterocyclyl, araJkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkylthio Each R' and Z is, independently, hydrogen, a straight- or branched-chain, saturated or unsatuiated C1 to Chalky] or heteroalkyl group, C1 to Cs saturated 01 unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstitutcd aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a d to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl. carbonyl, carboxylate, ester, formyl, acyl, tlnocarbonyl, tbioester. thioacetate, thioformate, alkoxyl, pbosphoryl, phosphonate, phosphmate, ammo, amido, dmidine, lmute, cyano, nitro, azido, sulflrydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, hetcrocycJyl, aralkyl, aromatic moiety, heteroaromatic moiety, immo, silyl, ether, and alkylthio Each L is, independently, a straight- or branched-cham, saturated or unsaturated C1 to C2o alkyl or heteroalkyl group, C3 to C$ saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstitutcd alkaryl wherein the alkyl is a C\ to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioebter, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate. amino, amido, amidine, rmine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkylthio R* is a linking moiety formed from the reaction of R with a biologically-active compound or precursor thereof, and B is a biologically-active compound, 01 precursor thereof, after conjugation with R For example, R may be a moiety selected from the group consisting of carboxyhc acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydraxide, protected hydrazide, succinimidyl, lsocyanate, lsothiocyanate, dithiopyndme, vinylpyndine, iodoaceramide, epoxide, hydroxysuccmirmdyi, azole, malermide, sulfone, allyl, vmylsulfone, trebyl, sulfo-N-succmimidyl, dione, mesyl, tosyl. and glyoxal. In another embodirofcnt, P is a polyethylene glycol having the structure of Formula II' (Formula Removed) wherein E is hydrogen, a straight- or branched-chaiu C1 to C10 alkyl group, or a detectable label, and a is an integer from 4 to 10,000 In this embodiment, E may be methyl. In still another aspect, P is a polyethylene glycol having the structure of Formula II- (Formula Removed) wherein E is a moiety suitable for farming a bond between the compound of Formula XV and a biologically-active compound or precursor thereof and a is an integer from 4 to 10,000. Here, E may be selected from die group consisting of carboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, Irydroxy, protected hydroxy, carbonate, alkenyl, acrylate. methacrylate. acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazidc, succinimidyl, isocyanate lsothiocyanate, dithiopyridme, vinylpyridine, lodoacetarmde, epoxide, hydroxysuccimmidyl, azole. maleimide, sulfonc, allyl, vinylsulforie, tresyl, sulfo-N-succinimidyl, dione, mesyl, tosyl, and glyoxal. Additionally, E may have the structure according to' (Formula Removed) wherein Q is a C1 to Cg saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, (including fused bicychc and bridged bicyclic ring structures), a substituted or unsubstituted aryl or heteroaryl group, or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl. tmocarbonyl, thioestcr, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinatc, amino, amido, amidme, imine, cyano, mtro, azido, suifhydryl, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aTalkyl, aromatic moiety, heteroaromatic moiety, lmino, silyl, ether, and alkylthio; each X, Y, Z, m, and n are, independently, as defined, each W is, independently, hydrogen or a C\ to C7 alkyl; and R"' is a moiety suitable for forming a bond between the compound of Formula III and a biologically-active compound or precursor thereof In another embodiment, E can have the structure according to Formula IV: (Formula Removed) wherein X, Z and n are as defined; each W is. independently, hydrogen or a C1 to C7 alkyl; and R'' is a moiety suitable foT forming a bond between the compound of Formula IV and a biologically-active compound or precursor thereof. In still another embodiment, R1' is chosen from the group consisting of carboxylic acid, ester, aldehyde, aldehyde hydrate, acctal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylale, metliacrylate, acrylamidc, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succmimidyl, isocyanate, isothiocyanate, dithiopyndine, vinylpyridine, lodoacetamide, epoxide, hydroxysueeinimidyl, azole, rnaleimidc, sulfone, allyl, vmylsulfone, tresyl, sulfo-N-succiiiirmdyl, dione, mesyl, tosyl, and glyoxal Likewise, in other embodiments, R'' may selected from the group consistmg of carboxyhc acid, ester, aldehyde, aldehyde hydrate, acctal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamide. substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succinimi'dyl, isocyanate, lsofhiucyanate, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, hydroxysuccmimidyl, azole. maleimide, sulfone, allyl, vmylsulfone, tresyl, sulfo-N-succinimidyl, dione, mesyl, tosyl, and glyoxal. In other embodiments, E is a detectable label For example, E may be selected from the group consistmg of radioactive isotopes, fluorescent moieties, phosphoiesoent moieties, chemiluirunescent moieties, and quantum dots. In another aspect, the invention relates to a composition having the structure according lo Formula XVI: (Formula Removed) where m is 0 or 1, n is 0 or an integer from 1 to 5, P is a polyalkylene glycol polymer, X and Y are independently 0, S, CO, CO>, COS, SO, SO2, COM', SO2NR\ or NR'. Ti and T> are, independently, absent, or a straight- or branched-chain, saturated or unsaturated C1 to C20 alky] or heteroalkyl group, and each R' and Z is independently hydrogen, a blraight- 01 branched-cham, saturated or unsaturated C1 to Q20 alkyl or heteroalkyl group, d is 0 or an integer from 1 to 4, and each L is, independently, a straight- or branched-cham, saturated or unsaturated C\ to C20 alkyl or heteroalkyl group, C3 to C1 saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heleroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C\ to C20 saturated or unsaturated alkyl or heteroalkaryl group. The subsntuents are selected from halogen, hydroxyl, carbonyl, carboxylate, ester, formy], acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphmate, ammo, amido, amidine, imme, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl. heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, sity], ether, and alkylthio grnups R* is a linking moiety formed from the reaction of R with a biologicall>-acri\e compound or precursor thereof, and B is a biobgically-actrvc compound, or precursor thereof, after conjugation with R For example, R may be a moiety selected from the group consisting of carboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylatc, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydwide, succmimidyl, lsocyanate, isothiocyanate, dithiopyndme, vinylpyridine, lodoacetamide, epoxide, hydroxysticcmimidyl, azole, maleimide, sulfone, ally!, \inylsu!fone, tresyl, suIfo-N-succinimidyl, dione, mesyl, tosyl, and glyoxal In one embodiment, R* is a methylene group and B is a biologically-acti\e molecule having an amino group, where the methylene group forms a bond with the ammo group on B In certain embodiments, the amine is the amino terminus of a peptide, an amine of an amino acid side cbam of a peptide, or an amine of a glycosylation substituent of a glycosylated peptide. For example, the peptide can be an interferon, such as interferon-beta. e g.. interferon-beta-la In some embodiments, the compound according to Formula XVI has a structure according to Formula XVII (Formula Removed) where Pisa pulyalkylene glycol polymer, Z is hydrogen, a straight- or branched-chain, saturated or unsaturated C\ to C20 alkyl or heterualkyl group, n is 0 or an integer from 1 to 5. R* is a linking moiety formed from the reacuon of R with a biologically-active compound or precursor diereof, and B is a biologically-active compound, or precursor thereof, after conjugation with R For example, R may be a moiety selected from the group consisting of carhoxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succinirmdyl, isocyanate, isothiocyanate, dithiopyndine, vinylpyridme, iodoacetamide, epoxide, hydroxysuccinimidyl, azole, maleimide, sulfone, ally], vinylsulfone, tre&yL suIfo-N-succinimidy], dione, mesyl, tosyl, and glyoxal. In one embodiment, R* of Formula XVT1 is a methylene group and B is a biologically-active molecule having an amino group, where the methylene group forms a bond with the amino group on B, In certain embodiments, the amine is the amino terminus of a peptide, an amine of an amino acid side chain of a peptide, or an amine of a glycosylate substituent of a glycosylated peptide For example, the peptide can be an interferon, such as interferon-beta, e.g., interferon-beta-la In other embodiments, the compound according to Formula XVT has a structure according to Formula Win (Formula Removed) where P is a pol)'alkylene glycol pol}TneT, R* is a linking moiety, B is a biologically-actrve molecule, and n is one or two In one embodiment, R* of Formula XVIII is a methylene group and B is a biologically-actrve molecule having an amino group, where the methylene group forms a bond with the amino group on B. In certain embodiments, the amine is the amino terminus of a peptide, an amine of an amino acid side chain of a peptide, or an arnine of a glycosylation substituent of a glycosylated peptide For example, the peptide can be an interferon, such as mterferon-beta, e.g., mterferon-beta-la In certain embodiments of the compound according to Formula XVI, P is a polyethylene glycol having the structure of Formula II (Formula Removed) wherein E is hydrogen, a straight- or braiiched-cham C1 to C20 alky 1 (e.g, methyl) group, a detectable label, or a moiety suitable for forming a bond between the compound of Formula XVI and a biologic ally-active compound or precursor thereof and a is an integer from 4 to 10,000, When E is a detectable label, the label can be, for example, a radioactive isotope, fluorescent moiety, phosphorescent moiety, chemilumineseent moiety, or a quantum dot In another embodiment, where E is a moiety suitable for forming a bond between the compound of Formula XVI and a biologically-active compound or precursor thereof, E is chosen from carboxyhc acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succirumidyl, isocyanate, isothiocyanate, dithiopyndme, vinylpyndine, lodoacetamide, epoxide, hydroxysuccimmidyl, azole, maleimide, sulfone, allyl, vinylsulfone, tresyl, sulfo-N-suceimmidyl, dione, mesyl, tosyl, and glyoxal moieties In another embodiment, E has the structure according to Formula IH or Formula IV (Formula Removed) Z where Q is a C3 to C§ saturated or unsaturated cyclic alkyl or cyclic heteroalkyl (including fused bioydic and bridged bicyclic ring structures), a substituted or unsubstituted aryl or heteroaryj group, or a substituted or unsubstituted alkaryl; thtj alkyl is a C\ to C20 saturated or unsaturated alkyl or hcteroalkaryl group, and the substituents can be of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, rhioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, bctcrocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, or alkylthio. X, Y, Z, m, and n are as defined, and each W is, independently, hydrogen or a C] to C7 alkyl; and R" is a moiety suitable for forming a bond between the compound of Formula III and a biologically-active compound or precursor thereof, and R'"' is a moiety suitable for forming a bond between the compound of Formula IV and a biologically-autive compound or precursor thereof In certain embodiments, R'" and R'" can be the same as or different from R, and are chosen irona carboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamidc, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succmimidyl, isocyanate, isotliiocyanatc, dithiopyndtne, vvnylpyridine, iodoacetamide, epoxide, hydToxysuccinimidyl, azole, rnaleirnide, sulfone, ally], vmylsulfone, tresyl, sulfo-N-succmimidyl, dione, mesyl, tosyl, and glyoxal moieties. In other embodiments of the compound according to Formula XVI, the compound can have the structure according to Formula XIX: (Formula Removed) wherein P is a palyalkylene glycol polymer, each n and u are, independently, zero or an integer from one to five, Z is hydrogen, a straight- or branched-chain, saturated or unsaturated C1 to C20 alkyl or heteroalkyl group R* is a linking moiety formed from the reaction of R with a biologically-actrve compound or precursor thereof, and B is a biologically-ach ve compound, or precursor thereof, after conjugation with R In one embodiment, R* of Formula XIX is a methylene group and B is a biologically-active molecule having an amino group, where the methylene group forms a bond with the amino group on B. In certain embodiments, (he amine is the ammo terminus of a peptide, an amine of an amino acid side chain of a peptide, or an amine of a glycosylation substituent of a glycosylated peptide. For example, the peptide can be an interferon, such as lntcrferon-beta, e.g., interferon-beta-la In another aspect, the invention relates to a composition according to Formula XX (Formula Removed) where m is 0 or 1, d is 0 or an integer from 1 to 4, a is an integer from 4 to 10,000, and n is 0 or an integer from 1 to 5 Each X and Y is independently O, S, CO, CO2, COS, SO, SO2, CONR'. SO2NR', or NR", or NR", T] and T2 are, independently, absent, or a straight- or branched-chain, saturated or unsaturated C1 to C20 alkyl or heteroalkyl group, and each R' and Z is independently hydrogen, a straight- or branched-chain, saturated or unsaturated C1 to C^ alkyl or heteroalkyl group. W hen present, each L is, independently, a straight- or branched-cham, saturated or unsatuiated C\ to C'20 alkyl or heteroalkyl group, C3 to C« saturated or unsaturated cyclic alkyl oi cyclic lieteroalkyi, a substituted or unsuhstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group. The substituents are selected from halogen, hydroxyl, carbonyl. carboxylate, ester, formvl, acyl, thiocarbonyl, thioestcr, thioacetate, thiofonnate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amiJine, unine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfoiiyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkyltmo. Q is a C3 to C8 saturated or unsaturated cyclic alkyl or cyclic heteroalkyl (including fused bicyclic and bridged bicyclic ring structures), a substituted or unsuhstituted aryl or heteroaryl group, or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group The substituents can be halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl. thiocarbonyl. thioester. thioacetate, thioformate. alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidine, lmine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, or alkylthio. Each W is, independently, hydrogen or a C1 to C7 alky] R* and R** are, independently, linking moieties formed from the reaction of R and R" with a biologically-active compound or precursor thereof, and B and B' are each a biologically-active compound, or precursor thereof, after conjugation with R and R'\ respectively In some embodiments, B and B' are the same type of biologically-active compound. In other embodiments, B and B% are different biologically-active compounds In still other embodiments, B and B' are the same biologically active molecule. In additional embodiments. R* and R** are the same. In other embodiments, R* and R** are different. In another aspect, the invention relates to a composition according to Formula XXI' (Formula Removed) where m is 0 or 1, d is 0 or an integer from 1 to 4, a is an integer from 4 to 10,000. and 11 is 0 or an integer from 1 to 5 X and Y are independently O, S, CO, CO2, COS, SO, SO2, CONR',. SO2NR', or NR', T1 and Tz are, independently, absent, or a straight- or branched-chain, saturated or unsaturated C1 to C20 alkyl or heteroalkyl group, each R' and Z is, independently, hydrogen, a straight- or branched-cham, saturated or unsaturated C; to C20 alkyl or heteroalkyl group When present, each L is, independently, a straight- or branched-chain, saturated or unsaturated C1 to C20alky! or heteroalkyl group, C3 to C8 saturated or unsaturated cyclic alkyl or cyclic heteroalkYl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the substiruents are selected from halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphtnate, amino, amido, aimdine, mnne. cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonvl, heterocyclyl, aralkyl, aromatic moiety, hetero aromatic moiety, rnimo. silyl, ether, and alkylthio, and each W is, independently, hydrogen or a C1 to C7 alky] R* and R** are, independently, linking moieties formed from the reaction of R and R" with a biologically-active compound or precursor thereof, and B and B' are each a biologicalhy-active compound, or precursor thereol, after conjugation with R and R", respectively. In some embodiments, B and B' are the same type of biologically-active compound In other embodiments, B and B' are different biologically-active compounds. In stdl other embodiments. B and B' are the same biologically active molecule. In additional embodiments, R* and R** are the same In other embodiments, R* and R** arc different In another aspect, the invention involves a composition having the structure according to Formula XXII' (Formula Removed) wherein P is a polyalkylene glycol polymer, X is O. S, CO, CO2, COS, SO, SO2, CONR\ SO2iNR', orNR', R' is hydrogen, a straight- or branched-chain, saturated or unsaturated Q to C20 alkyl or heteroalkyl group, C3 to C\ saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherem the alkyl is a C\ to C20 saturated or unsaturated alkyl or heteroalkaryl group, wheiein the substiruents are selected from the group consisting of halogen, hydro Kyi, carbonyl. carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl. phosphoryl, phosphonate, phosphinate, amino, amido, amidine, lmme, cyano, mtro, azido, sulfliydiyl, sulfate, sulfonate, sulfamoyl, sulfonamide sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkyltbio, each Z and Z' is independently hydrogen, a straight- or branched-chain, saturated or unsaturated C1 to C2r> alkyl oi heteroalkyl group, C3 to Cg saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heleroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to do saturated or unsaturated alkyl or heteroalkaryl group, wherein the subshtuents arc selected from the group consisting of halogen, hydroxyl, carbonyl. carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidine, imme, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, hctcrocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkylthio, provided that at least one Z or V is not hydrogen; R* is a linking moiety, B is a biologically-active molecule, each n is 0 or an integer from 1 to 5; and p is 1,2, or 3 In a further aspect, the invention involves a composition having the structure according to Formula XXIIa. (Formula Removed) wherein P is a polyalkylene glycol polymer, X is O, S, CO, CO?, COS. SO, SO2, CONR', SO2NR\ or NR'; and n is 0 or an integer from 1 to 5 R' is hydrogen, a straight- or branched-cham, saturated or unsaturated C1 to C20 alkyl or heteroalkyl group, C3 to Cs saturated OT unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a Ct to CM saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents arc selected from the group consisting of halogen, hydroxyl, carbonyl, caTboxykie, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidme, inline, cyano, mtro, azido, sulfliydiyl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl. heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, hnino, silyl, ether, and alkylthio, Z is a straight- or branched-chain, saturated or unsaturated Ct to C30 alkyl or heteroalkyl group, C3 to C8 saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted OT unsubsfatuted aryl or heteroaryl group or a substituted or unsubshtuted aikaryl wherein the alkyl is a C\ to C20 saturated or unsaturated alkyl or hetcroaJkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphorate, phosphinatc, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkylthio R* is a linking moiety formed from the reaction of R with a biologically-active compound or precursor thereof, and B is a biologically-active compound, or precursor thereof, after conjugation with R. In one embodiment, R* is formed from the reaction of a moiety selected from the group consisting oi carboxyhc acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted 01 unsubstituted amine, protected amine, hydrazide, protected hydrazide, succinimidyl, isocyanate, isothiocyanate, dithiupyndine, vinylpyridine, iodoacetamide, epoxide, hydroxysuccimmidyl, azole, maleimidc, sulfone, allyl, vinylsulfone, tresyl, sulfo-N-succinJmidyl, dione, mesyl, tosyl, and glyoxal with a biologically-active compound or precursor thereof In an additional embodiment, P is a polyethylene glycol having the structure of Formula II. (Formula Removed) wherein E is hydrogen, a straight- or branched-chain C\ to C20 alkyl group, or a detectable label, and a is an integer from 4 to 10,000 In this embodiment, E may be methyl. In another embodiment, P is a polyethylene glycol having the structure of Formula 11. (Formula Removed) wherein E is p moiety suitable for forming a bond between the compound of Formula II and a biologically-active compound or precursor thereof and a is an integer from 4 to 10,000, In this embodiment. E may bind to a biologically-active compound or precursor thereof otlier than B In other embodiments, E forms an additional bond to the biologically-active compound B In various embodiments. E may be selected from the group consisting of carboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylatc, methacrylate, acrylamide, substituted or unsubshtuted thiol, halogen, substituted or unsubshtuted amine, protected amine, hydrazide, protected liydrazide, succinimidyl, lsocyanate, isothiocyanate, dithiopyndine, vmylpyndme, lodoacetamide, epoxide, hydroxysuccinirnidyl, azoic, maleimide, sulfone, allyl, vinylsulfone, tresyl. sulfo-N-succmimidyl, dione, ruesyl, tosyl, and glyoxal. In otlier embodiments, E has the structure according to Formula III' (Formula Removed) wherein F is a polyalkylenc glycol polymer; each X and Y is independently O, S, CO. CO2, COS, SO, SO2, CONE.', SOiNR\ or NRQ is a C3 to Cg saturated or unsaturated cyclic alkyl or cyclic heteroalkyl (including fused bicychc and bridged bicyclic ring structures), a substituted or unsitbstituted aryl or heteroaryl group, or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, tliioacetate, thioformate, alkoxyl, phosphoryl. phosphonate, phosphtnate, ammo, amido, amidine, inline, cyano, nitro, azido, sulfirydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, araLkyl, aromatic moiety, heteroaromatic moiety, tmino, silyl, ether, and alkylthio; R' and each Z are independently as described above; misOor 1; each n is independently 0 or an integer from 1 to 5, R" is a moiety suitable for forming a bond between the compound of Formula III and a biologically-active compound or precursor thereof, and each W is, independently, hydrogen or a C1 to C7 alkyl In a further embodiment, E has the structure according to Formula IV: (Formula Removed) wherein each X, Z and n are, independently, as defined, each W is, independently, hydrogen or a C1 to C7 alkyl, and R'" is a moiety suitable for torming a bond between the compound of Formula IV and a biologically-active compound or precursor thereof In still further embodiments, R'" is chosen from the group consisting of carboxyhc acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, metliacrylate, acryiamide, substituted or unsubstitutcd thiol, halogen, substituted or unsubshtuted amine, protected amine, hydrazide, protected hydrazide, succinirmdyl, isocyanatc, isothiocyanate, dithiopyridine, vinylpyridine, lodoacetamide, epoxide, hydroxysuctmimidyl, azole, maleimide, sulfone, allyl, vinylsulfone, tresyl, sulfo-N-succuumidyl, dione, mcsyl, tosyl, and glyoxal. In yet other embodiments, R'" is chosen from the group consisting of carboxyhc acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkerry], acrylate, melhacrylate, acryiamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succmimidyl, isocyanate, isothiocyanate, dithiopyridine, vinylpyridine, lodoacetamide, epoxide, hydroxysuccmimidyl, azole, maleimide, sulfone, allyl, vinylsulfone, tresyl, sulfo-N-succmimidyl, dione, mesyl, tosyl, and glyoxal. In additional embodiments, E is a detectable label. For example, E may be selected horn the group consisting of radioactive isotopes, fluorescent moieties, phosphorescent moieties, chemiluminescent moieties and quantum dots In another embodiment, R* is methylene and B is J biologically-active molecule attached via an amine Foi example, the amine is the ammo terminus of a peptide In a further embodiment, the peptide is an interferon such as mterferon-beta-la In anothei embodiment, the invention is a composition having the structure according to Formula XXIII (Formula Removed) wherein n, a, R* B, and Z are as defined above In one additional embodiment, Z is methyl and n is one In still a furthei aspect, the rn\ ention involves a composition according to Formula XXIV. (Formula Removed) B'—R—LH-(CH2)n—lY^—Q—X-CW.CWJ-IO-CHJCH^—X—(CH2)/ R Z wherein m is 0 or 1, a is an integer from 4 to 10,000. and each n is independently zero or an integer from 1 to 5. Each X and Y is independently 0, S, CO, CO2, COS, SO, SO2, CONR*, SO^NR', or NR\ each R' and Z is, independently, hydrogen, a straight- or branchcd-cham, saturated or unsaturated C1 to CM alkyl or hctcroalkyl group; and each W is, independently, hydrogen or a C| to C1 alky! Q is a C1 to Cg saturated or unsaturated cyclic alkyl or cyclic heteroalkyl (including fused bieyclic and bridged bicyclic ring structures), a substituted or onsubstitutcd aryl or heteroaryl group, or a substituted or unsubstitutcd alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the substiruents are selected from the group consisting of halogen, hydroxyl, tarbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thiofomiate, alkovyl, phosphor)'!, phosphonate, phosphinate. amino, amido, amidine, imine, cyano, nitro, azido, sulftiydryi, sulfate, sulfonate, sulfamoyl, sulfonanudo, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, hcteroaromatic moiety, imrno, silyl, ether, and alkylthio. R* and R** are, independently, Unking moieties formed from the reaction of R and R' with a biologically-active compound or precursor thereof, and B and B' are each a biologically-active compound, or precursor thereof, after conjugation with R and R'\ respectively In some embodiments. B and B' are the same type of biologically-active compound. In other embodiments. B and B' arc different biologically-active compounds In still other embodiments, B and B1 are the same biologically active molecule In additional embodiments, R* and R** are the same In other embodiments, R* and R** are different. In a further aspect, the invention involves a composition according to Formula XXV (Formula Removed) wherein X is 0, S, CO, CO2, COS, SO, SO2, CONR', SQ.NR , orNR', a is an integer from 4 to 10,000, and each n is independently 0 or an integer ironi 1 to 5. Each aDd Z is independently hydrogen, a straight- or biancbed-chain, saturated or unsaturated C\ to Caj alkyl or hetemalkyl gruup, and each W is, independently, hydrogen or a C] to C7 alkyl R* and R** are, independently, linking moieties formed from the reaction of R and R" with a biologically-active compound or precursor thereof, and B and B' are each a biologically-active compound, or precursor thereof, after conjugation with R and R"', respectively In some embodiments, B and B' are the same type of biologically-active compound. In other embodiments, B and B' are different biologically-active compounds In still other embodiments, B and B' are the same biologically active molecule In additional embodiments, R* and R** are the same. In other embodiments, R* and R1"* are different. The invention also involves a pharmaceutical composition containing the compositions of the invention along with a pliarmaceutically-acceptablc earner. In various embodiments, the pharmaceutical composition also contains an additional biologically-active agent. For example, the biologically-active agent may be select from the group consisting of a peptide, peptide analog, protein, enzyme, small molecule, dye, lipid, nucleoside, oligonucleotide, obgonucleotide analog, sugar, oligosaccharide, cell, virus, liposome, microparticle, surface, and a micelle In another embodiment, the biologically-active agent is an antiviral agent. In another aspect, the invention relates to a composition comprising the product of the reaction of the compound of Formula I and a biologically-active compound or a precursor thereof (B). In one embodiment, the composition has the structure according to Formula XTV- (Formula Removed) Z where all variables are as defined above, and R* is a linking moiety formed by the reaction of R with a reactive moiety on the biologically-active compound or precursor thereof, and B is a biologically-active compound or precursor thereof. In another aspect, the invention relates lo a composition comprising the product of the reaction of the compound ot Formula V and a biologically-active compound or a precursor thereof In one embodiment, the composition has the structure according to Formula XV: (Formula Removed) (L)d where all variables are as defined above, R* is a linking moiety formed by the reaction of R with a reactive moiety on the biologically-active compound or precursor thereof; and B is a biologically-active compound or precursor thereof. In yet another embodiment, the composition has the structure according to Formula XX or XXI (Formula Removed) where all variables are as defined above, each V> is, independently, hydrogen or a C1 to CV alkyl, R* is a linking moiety formed by the reaction of R with a reactive moiety on the biologically-active compound, B, or precursor thereof, R^* is a linking moiety formed by the reaction of R" or R"" with a reactive moiety on the biologically-active compound, B\ or precursor thereof, and B and B1 are, independently, a biologically-active compound or precursor thereof In some embodiments, B and B' are the same type of biologically-active compound In other embodiments, B and B: are different biologically-active compounds. In still other embodiments, B and B' are the same biologically active molecule. In additional embodiments, R* and R*+ are the same. In other embodiments, R* and R** are different In another aspect, the invention relates to a composition comprising the product of the reaction of the compound Formula VI and a biologicallv-actrve compound or a precursor thereof In one embodiment, the composition has the structure according to Formula XVI (Formula Removed) where all variables are as defined above, R* is a linking moiety formed by the reaction of R with a reactive moiety on the biologically-active compound or precursor thereof, and B is a biologically-active compound or precursor thereof In another aspect, the invention relates to a composition comprising the product of the reaction of the compound of Formula VTI and a biologically-acnve compound or a precursor thereof In one embodiment, the composition has the structure according to Formula XVII: (Formula Removed) where all variables are as defined above, R* is a linking moiety formed by the reaction of R with a reactive moiety on the biologically-active compound or precursor thereof; and B is a biologically-active compound or precursor thereof In another aspect, the invention relates to a composition comprising the product of the reaction of the compound of Formula VIII and a biologically-acnve compound or a precursor thereof In one embodiment, the composition has the structure according to Formula XVHI: (Formula Removed) where all vanables are as defined above, R* is a linking moiety formed by the reaction of R with a reactive moiety on the biologically-active compound or precursor thereof, and B is a biologically-active compound or precursor thereof In another aspect, the invention relates to a composition comprismg the product of the reaction of the compound of Formula IX and a biologically-active compound or a precursor thereof. In one embodiment, the composition has the structure according to Formula XIX" (Formula Removed) where all vanables are as defined above, R* is a linking moiety formed by the reaction of R with a reactive moiety on the biologically-active compound or precursor thereof; and B is a biologically-active compound or precursor thereof In another aspect, the invention relates to a composition comprising the product of the reaction of the compound of Formula X and a biologically-active compound or a precursor thereof. In one embodiment, the composition has the structure according to Formula XXTJ" (Formula Removed) Z where all variables are as defined above, R* is a linking moiety formed by the reaction of R with a reactive moiety on the biologically-active compound or precursor thereof, and B is a biologically-active compound or precursor thereof In another embodiment, the composition has the structure the structure according to Formula XXIV. (Formula Removed) where all variables are as defined above, each W is. independently, hydrogen or a C| to C7 alkyl. R* is a linking moiety formed by the reaction of R with a reactive moiety on the biologicalty-acave compound, B, or precursor thereof, R** is a linking moiety formed by the reaction of R,% with a reactive moiety on the biologically-active compound, B", or precursor thereof; and B and B* are, independently, a biologically-dulne compound or precursor thereof In some embodiments, B and B1 are the same type of biologically-active compound In other embodiments. B and B' are different biologically-active compounds. In still other embodiments, B and B' are the same biologically active molecule. In additional embodiments, R* and R*+ are the same In other embodiments, R* and R** are different In other embodiments, the composition has the structure according to Formula XXV (Formula Removed) where all variables are as defined in claims above, each W is, independently, hydrogen or a C1 to C7 alkyl R* and R** are, independently, linking moieties formed from the reaction of R and R" with a biologically-active compound or precursor thereof, and B and B' are each a biologically-active compound, or precursor thereof, after conjugation with R and R", respectively In some embodiments, B and B' are the same type of biologically-active compound. In other embodiments, B and B' are different biologically-active compounds, In still other embodiments. B and B' ai-e the same biologically active molecule. In additional embodiments, R* and R** are the same In other embodiments, R* and R** are different. In another aspect, the invention involves a method of treating a patient with a susceptible viral infection, comprising administering to the patient an effective amount of a composition having the structure according to Formula XIV. (Formula Removed) wheiein Pisa polyalkylene glycol polymer, X and Y are independently 0, S, CO, COj, COS, SO, SO:, CONR\ SC^NR', orNR'; Q is a C} to C$ saturated or unsaturated cyclic alky] or cyclic heteroalkyl (including fused bicychc and bridged bicychc nag structures), a substituted or unsubstituted aryl or heteruaryl group, or a substituted or unsubstituted alkar> 1 wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the substiiuents are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, forrnyl, acyt, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, pho&phoryl, phosphorate, phosphinate, amino, amido, amidine, irmne, cyano, nitro, azido, sulihydry], sulfate, sulfonate, sulfamoy], sulfonamido, sulfonyl, heterocyclyl, aralkyl. aromatic moiety, heteroaromatic moiety, imino, sjlyl, ether, and alkylthio, each R', Z and Z' is independently hydrogen, a straight- 01 branched-chain. saturated or unsaturated C) to Qo alkyl or heteroalkyl group, C3 to Cs saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to Ca> saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents arc selected from the .group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphorate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralky!, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkylthio, R* is a linking moiety. B is a biologically-active compound or precursor thereof, in is 0 or 1; each n is 0 or an integer from 1 to 5, and pis 1,2, or 3 In a further aspect, the invention involves a method of treating a patient with a susceptible viral infection by administering to the patient an effective amount of a composition having the structure according to Formula XTVa (Formula Removed) wherein P is a polyalkylene glycol polymer, m is 0 or 1; and n is 0 or an integer from 1 to 5 X and Y are independently 0, S, CO, CO2, COS, SO, SO2, CONR', SO2NR', or NR', and Q is a r3 to C8 saturated or unsaturated cyclic alkyl or cyclic heteroalkyl (including fused bicychc and bridged bicyclic rmg structures), a substituted orunsubshtuted aryl or heteroaryi group, or a substituted or unsubsbtuted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkary 1 group, wherein the subsrituenls are selected from the group consisting of halogen, hydroxyl, carbony], carboxylate, ester, formyl. acyl, thiocarbonyl, thioester, thioacetata, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinafe, amino, aroido, amidine, imme, cyano, nitro, azido, wilfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkylrhio. Each R' and Z is independently hydrogen, A straight- or branched-chain, saturated or unsaturated C1 to C20 alkyl or heteroalkyl group, C3 to Cs saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryi group or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the subsbtuents are selected from the group consisting of halogen, hydroxyl, carbony], carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, truoacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, ammo, amido, amidine, iminc, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, hcterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkylthio, R* it. a linking moiety formed from me reaction of R with a biologically-active compound or precursor thereof, and B is a biologicaDy-active compound, or precursor thereof, after conjugation with R. In one embodiment, B is a biologically-activepepbde such as interferon. For example, this interferon may be interferon-beta-la In further embodiments, the composition also includes a biologically-uctive agent selected from the group consisting of a small molecule antnral, a nucleic acid antiviral and a pephdic antiv iral For example, the antiviral agent may be selected from the group consisting of ribavirin, levovinn, 3TC, F i'C, MB686, zidovudine, acyclovir, gancyclovir, wrarnidc, VX-497, VX-9SO, and ISIS-14803 In various embodiments the viral infection in need of treatment is chrome hepatitis C In an additional aspect, the invention involves a method of treating a patient with a susceptible vnal infection by administering to the patient an effective amount of a composition having the structure according to Formula XV: (Formula Removed) wherein P is a polyalkylene glycol polymer, m is 0 or 1; d is 0 or an integer from 1 to 4; n is 0 or an integer from 1 to 5; and X and Y are independently 0, S, CO, CO2, COS, SO, SO2, CONK\SO2Nir.orNRTi and T2 are, independently, absent, or a straight- or branched-chain, saturated or unsaturated C1 to C20 alkyl or heteroalkyl group, a C3 to C8 saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstitutcd aryl or hctcroaryl group, or a substituted or unsubstituted alkaryl wherein the alkyl is a C\ to C10 saturated OT unsaturated alkyl or heteroalkaryl group, wherein tire substituents are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester. thioacetate, thioformate. alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidine, mnne, Lyano, mtro. azidu, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteioaromatic moiety, imino, silyl, ether, and alkylthio. Each R' and Z is independently hydrogen, a straight- or branched-chain, saturated or unsaturated C| to C20 alky] or heteroalkyl group, C3 to Cg saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstitutcd aryl or heteroaryl group or a substituted or unsubstitated alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, carbonyl. carboxyiatc, ester, formyl, acyl. thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, ammo, amido, amidine, imme, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonanudo, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkylthio Each L is, independently, a straight- or branched-chain, saturated or unsaturated C\ to C20 alkyl or heteroalkyl group, C3 to Ca saturated or unsaturated eyebe alkyl or cyclic heteroalkyl, a substituted or unt>ubstituted aryl or heteroaryl group or a substituted or unsubsntuted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteioalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinatc, ammo, amido, amidine, lmrae, cyauo, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfaraoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, unino; silyl, etlier, and alkylthio, R* is a linking moiety formed from the reaction of R with a biologically-active compound or precursor thereof, and B is a biologically-active compound, or precursor thereof, after conjugation with R Tn various embodiments, B is a biologically-active peptide such as interferon. For example, in one embodiment, B is interferon-beta-la, In another embodiment, the composition further contains a biologically-active agent selected from the group consisting of a small molecule antiviral, a nucleic acid antiviral and a peptidic antiviral. In other embodiments, the antiviral agent may be selected from the group consisting of ribavirin, levovirin, 3TC, FTC, MB686, zidovudine, acyclovir, ganciclovir, viramide. VX-497, VX-950, and ISIS-14803. In addition, the viral infection can be chronic hepatitis C In a further aspect, the invention involves a method of treating a patient with a susceptible viral infection by administering to the patient an effective amount of a composition having the structure according to Formula XVI (Formula Removed) where P is a polyalkylene glycol polymer; m is 0 or 1, d is 0 or an integer from 1 to 4; n is 0 or an integer fiom 1 to 5, X and Y arc independently O. S, CO, CO>, COS, SO, SO2, CONR\ SO2NR', orNR'; Tj and T2 are, independently, absent, or a straight- or branched-chain, saturated or unsaturated Q to C20 alkyl or heteroalkyl group, and each R' and Z is independently hydrogen, a straight- or branched-chain, saturated or unsaturated C] to C20 alkyl or heteroalkyl group. Fach L is, independently, a straight- or branched-chain, saturated or unsaturated C1 to C20 alkyl or heteroalkyl group, C3 to Cg saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubshtuted aryl or heteroaryl group or a substituted or unsubshtuted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein tlie substituents are selected from the group consisting of halogen, hydroxyl, carbonyl, cafboxylate, ester, formyk acyk thiocarbonyl, tliioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphrnate, amino, amido, amidme, mime, cyano, nitio. azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl. heterocyclyl, aralkyl, aromatic moiety, Iieteroaromatic moiety, imino, silyl, ether, and alkylthio R* is a linking moiety formed from the reaction of R with a biologically-active compound OT precursor thereof, and B is a biologically-actrve compound, or precursor thereof, after conjugation with R In various embodiments, B is a biologically-active peptide such ai interferon For example, B maybe interferon-hela-la. In still further embodiments, the composition further contains a biologically-active agent selected from the group consisting of a small molecule antiviral, a nucleic acid antiviral and a peptidic antiviral For example, the antiviral agent may be selected from the group consisting of ribavirin, levovinn, 3TC, FTC, MB686, zidovudine acyclovir, gancyclovir, viramide, VX497 VX-950, and ISIS-14803, In another embodiment, tlie viral infection is chrome hepatitis C. In a further aspect, the invention involves a method of treating a patient with a susceptible viral infection by administering to the patient an effective amount of a composition having the structure according to Formula XX. (Formula Removed) wherem m is 0 or 1, d is 0 or an mteger from 1 to 4, a is an mteger from 4 to 10,000, and n is 0 or an integei from 1 to 5 Ladi X and Y is independently 0, S. CO, CO2, COS, SO, SO2. CONR', SO2NR', or NR', T| and T2 are, independently, absent, 01 a straight- or branched-cham, saturated or unsaturated C1 to C20 alky' or heteroalkyl group; each R' and Z is independently hydrogen, a straight- or branched-chain, saturated or unsaturated Q to C20 alky] or heteroalkyl group; and each W is, independently, hydrogen or a C1 to C7 alkyl. Each L is, independently, a straight- 01 branched-chain, saturated or unsaturated Q to C20 alkyl or heteroalkyl group. C3 to Cg saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or hcteroaryl group or a substituted or unsubstituted alkaryl wherem the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, caibonyl, carboxylate. ester, formyl, acyl, thiocarbonyl, thioester, thioacelate, thiofonnate. alkoxyl, phosphoryl, phosphonate. phosphmate, ammo, amido, amidme, mune, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl. heterocyclyl, aralkyl, aromatic moiety, heteroaroicatic moiety, lmmo, sily], ether, and alkylthio. Q is a C3 to Cg saturated or unsaturated cyclic alkyl or cyclic heteroalkyl (including fused bicyclic and bridged bicyclic ring structures), a substituted or unsubstituted aryl or hcteroaryl group, or a substituted or unsubstituted alkaryl wherein the alkyl is a C\ to C2o saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, uarbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thiofonnate, alkoxyl, phosphoryL, phosphonate, phosphmate, amino, amido, amidme, irnine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, sibyl, ether, and alkylthio. R* and R** are, independently, linking moieties formed from the reaction of R and R" with a hwlogically-active compound or precursor thereof, and B and B' are each a biologically-active compound, or precursor thereof, after conjugation with R and R'\ respectively In some embodiments, B and B' are the same type of biologically-active compound In other embodiments, B and B' are different biologically-active compounds In still other embodiments, B and B" are the same biologically active molecule. In additional embodiments, R* and R*+ are the same In other embodiments, R* and R** are different. In various embodiments, B is a biologically-active peptide such as interferon For example, in one embodiment, B is interferon-beta-la In other embodiments, the composition further contains a biologically-active agent selected from the group consisting of a small molecule antiviral, a nucleic acid antiviral and a pcptidic antiviral. For example, the antiviral agent may be selected from the group consisting of ribavirin, levovinn, 3TC, FTC, MB686. zidovudine, acyclovir, gnncyclovir, viramide, VX- 497,VX-950,andISIS-14803 In a further embodiment, the viral infection is chronic hepatitis C In a further aspect the invention involves a method of treating a patient with a susceptible viral infection by administering to the patient an effective amount of a composition having the structure according to Formula XXT (Formula Removed) where m is 0 or 1, d is 0 or an integer from 1 to 4; a is an integer from 4 to 10,000, each n is 0 or an integer from 1 to 5; each X and Y is independently 0, S, CO, CO?, COS, SO, SU2, CONR', SOiNR', or NR'; T[ and T2 aie, independently, absent, or a straight- or brancbed-chain, saturated or unsaturated C1 to C20alkyl or licteroalkyi group, each R' and Z is independently hydrogen, a straight- or branched-cham, saturated or unsaturated C1 to C20 alkyl or heteroalkyl group, and each W is, independently, hydrogen or a C1 to C7 alkyl Each L is, independently, a straight- or branched-chain, saturated or unsaturated C1 to Chalky! or heteroalkyl group. Q to Cg saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted 01 unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to do saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester. thioacetatc, thioformate. alkoxyl, phosphoryl, phosphonate, phosphmate, amino, amido, amidine, imine, uyano, mtro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfony], heterocyclyl, aralkyl, aromatic moiety, heteroaromauc moiety, imino, silyl, ether, and alkylthio R* and R** are, independently, linking moieties formed from the reaction of R and K" with a biologically-active compound or precursor thereof, and B and B' are each a hrologically-active compound, or precursor thereof after conjugation with R and R", respectively In some embodiments, B and B' are the same type of biologically-active compound In other embodiments, B and B' are different biologically-active compounds In still other embodiments, B and B' are the same biologically active molecule. In additional embodiments, R* and R** are the same. In other embodiments, R* and R** arc different In various embodiments, B is a biologically-active peptide such as an interferon For example, B may be is interferon-beta-la. In another embodiment, (he Lumposition further contains a biologically-active agent selected from the group consisting of a small molecule antiviral, a nucleic acid antiviral and a peptidic antiviral For example, the antiviral agent may be selected from the group consisting of ribavirin, levovirin, 3TC, FTC, MB686, zidovudine, acyclovir, gancyclovir, viramidc, VX-497,VX-950,andISIS-14803 In a further embodiment, the viral infection is chronic hepatitis C. In another aspect, the invention involves a method of treating a patient with a susceptible viral infection, comprising administering to the patient an effective amount of a composition having the structure according to Formula XXII (Formula Removed) wherein P is a polyalkylene glycol polymer, X is 0, S, CO, CO2, COS, SO, SO2. CONR', SO2NR', 01 NRR' is hydrogen, a straight- or branched-cham, saturated or unsaturated C\ to Cjn alkyl or heteroalkyl group, C3 to Cs saturated or unsaturated cyclic alkyl or cyclic hetcroalkyl, a substituted or unsubstitutcd aryl or heteroaryl group 01 a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherem the substituents are selected from the group consisting of halogen, hydro Kyi, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, Ihiuibnnate, alkoxyl, phosphory], phosphorate, phosphinate. ammo, amido, amidme, imine, cyano, citro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkylthio, each Z and V is independently hydrogen, a straight- or brancbed-chain, saturated or unsaturated C1 to C20 alkyl or heieroalk) 1 group, C3 to C? saturated or unsaturated cycfic'alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C} to do saturated or unsaturated alky] or heteroalkaryl group, wherein the substftucnts arc selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, forrnyl, acyl, duocarbonyl, fhioester, thioacetale, thioforniate, aikoxyl, phosphoryl, phosphorate, phosphraate, amino, amulo, amidine, inline, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclvl, aralkyl, aromatic moiety, heteroaromatic moiety, immo, silyl, ether, and alkylthio provided that at least one Z or V is not hydrogen, R* is a linking inoiety, B is a biologically-active molecule mis o or 1, each n is 0 or an integer from 1 to 5; and pis 1,2, or 3 In still another aspect, the invention involves a method of treating a patient with a susceptible viral infection, comprising administering to the patient an effective amount of a composition having the structure according to Formula XXUa (Formula Removed) Z where: 2 is a polyalkylcne glycol polymer, m is 0 or}, a is 0 or an integer from 1 to 5; X is 0, S, CO. CO2- COS, SO, SO2, CONR'. SO2NR\ orNR', and R is hydrogen, a straight- or branched-cham, saturated or unsaturated C1 to Cm alkyl or heteroalkyl group, C3 to Cs saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C| to C20 saturated or unsaturated alkyl or heteroalkaryl gioup, wherein the substituents are selected from the gioup consisting of halogen, hydroxy], carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester. thioacetale, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, ammo, arrudo, amidme. imine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclvl, aralkyl, aromatic moiety, heteroaromatic moiety, imino. silvl, elher, and alkylthio Z is a straight- or branched-cham, saturated or unsaturated C1 to C2U alkyl or heteroalkyl group, C3 to Cg saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or hetcroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxy], carbonyl, carboxylate, ester, foimyl, acvl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidine, iimne, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkylthio R* is a linking moiety formed from the reaction of R with a biologically-active compound or precursor thereof, and B is a biologically active compound, or precursor thereof, after conjugation with R In venous embodiments, B is a biologically-active peptide such as interferon. For example, B may be interferon-bcta-la In another embodiment, the composition further contains a biologically-active agent selected from the group consisting of a small molecule antiviral, a nucleic acid antiviral and a peptidic antiviral. For example, the antiviral agent may be selected from the group consisting of ribavirin, levovinn, 3TC, FTC, MB686, zidovudine, acyclovir, ganciclovir, vimmide. VX-497, VX-950, and 1SIS-14803 In a further embodiment, the viral infection is chronic hepatitis C In yet another aspect, the invention involves a method of treating a patient with a susceptible viral infection by administering to the patient an effective amount of a composition having the structure according to Formula XXIV (Formula Removed) Z where, m is, 0 or 1, a is an integer from 4 to 10,000; each n is independently 0 or an integer from 1 to 5, each X and Y is independently O. S, CO, CO2, COS, SO, SO2, CONR\ SO2NR\ orNR'. each R' and Z is independently hydrogen, a straight- or branched-cham, saturated or unsaturated C1 to C2o alkyl or heteroalkyl group, and each W is, independently, hydrogen or a C1 to Q alkyl Q is a C3 to C'8 saturated or unsaturated cyclic alkyl or cyclic hcteroalkyl (including fused bicyclic and bridged bicyclic nng structures), a substituted or unsubstitutcd aryl or heteroaryl group, or a substituted or unsubstituted alkaryl wherein the alkyl is a Q to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents jre selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, tliiocarbonyl. thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, mtro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfooamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, immo, silyl. ether, and alkylthio R* and R** are, independently, linking moieties formed from the reaction of R and R" with a biologically-active compound or precursor thereof, and B and B' are each a biologically-active compound, or precursor thereof, after conjugation with R and R*\ respectively In some embodiments, B and B1 are the same type of biologically-active compound In other embodiments, B and B' are different biologically-active compounds. In still other embodiments, B and B' arc the same biologically active molecule. In additional embodiments. R* and R** are the same In other embodiments. R* and R** are different. In various embodiments, B is a biologically-active peptide such as interferon. For example, B may be mterferon-beta-la In other embodiments, the composition further contains* a biologically-active agent selected from the group consisting of a small molecule antiviral, a nucleic acid antiviral and a peptidic antiviral For example, the antiviral agent may be selected from the group consisting of ribavirin, levovirin, 3 tC, FTC. MB686, zidovudine, acyclovir, gancyclovir, virarnide, VX-497, VX-950, and ISIS-14803. In still other embodiments, the viral infection is chronic hepatitis C In an additional aspect, the invention involves a method of treating a patient with a susceptible viral infection by adrmnistenng to the patient an effective amount of a composition having the structure according 10 Formula XXV- (Formula Removed) z wherein each W is, independently, hydrogen or a C1 to C7 alkyl; a is an integer from 4 to 10,000, each n is independently 0 or an integer from 1 to 5; X is O, S, CO, CO2, COS, SO, SO2. CONR', SO2NR'. or NR'; and each and Z is independently hydrogen, a straight- or branched-chain, saturated or unsaturated C1 to C;» alkyl or beteroalkyl group R* and R** are, independently, linking moieties formed from the reaction of R and R' with a biologically-active compound or precursor thereof, and B and B' are each a biologically-active compound, or precursor thereof, after conjugation with R and R", respectively. In some embodiments, B and B' are the same type of biologically-active compound In other embodiments, B and B' are different biologically-active compounds. In still other embodiments, B and B' are the same biologically active molecule In additional embodiments, R* and R** arc the same. In other embodiments, R* and R** are different. In various embodiments, B is a biologically-active peptide such as interferon. For example, B may be interferon-beta-la. In another embodiment, the composition lurther contains a biologically-active agent selected from the group consisting of a small molecule antiviral, a nucleic acid antiviral and a peptidic antiviral For example, the antiviral agent may be selected from the group consisting of ribavirin, kvovirfn, 3TC, FTC, MB686, zidovudine, acyclovir, gancyciovir, vframide, VX-497,VX-950,andISIS-14803 In still other embodiments, the viral infection is chronic hepatitis C The present invention is also concerned with a method of treating a patient suspected of having hepatitis C infection by administering to the patient a combination of any of the compositions of the invention and an antiviral agent In various embodiments, the composition and the antiviral agent are administered simultaneously, sequentially, or alternatively. In one embodiment, the antiviral agent is ribavirin. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting Other features and advantages of the invention will be apparent from the following detailed description, and from the claims BRIEF Description of the DRAWINGS The present invention will be further Understood from the following description with reference to the tables, in whii.li FIG. 1 is a reducing SDS-PAGE $d showing the punt> of unmod ificd IFN-[Ma and 20 kDa nxPEG FIG. 3 ii,.»trace of the size exclusion chromatography of 20 kDa tnPEG-O-m* rndh^lphmj'lnatdeh)'de-rni1idiJ)ed [FN-ß-1 a FIG. 4 is a reducing SDS-PAGfe gd showing the punty of uranodiGed l>N-£-la and 20 kDa mPEG-ß-|^j3yteceTaIdehyde-rnodified IFN-[i-1 a' I anc A 2 5 ug of 20 kDa mPEG-O^/^pbenylac^ldeb^raodified IFN-O-la; Lane B. 2,5 jig of unmodiaed fFN-O-U Lane C. inolecufer weight markers (from top to bottom; iOO kDa, 68 kDa, 45 kDa, 27 kDa, and 18 kDa, respectively J FIG 5 depicts traces of the size exclusion chromatography of 20 kDa mPEG-O-ß-phenylacetaldchydc-modiftcd IFN-O-Ia; Panel A: molecular weight standards; Panel B: 20 kDa iEPEG-0^-phenylacetaldehyde-rm»dtfied IFN-pVIa FIG. 6 is a reducing SDS-PAGE gel deputing the stability of 20 kDa mPEG-Cty-phcTrykcdaldehyde-modified IFN-ß- la: Lane A: molecular weight markers (front top to bottom; 10ft kDa, 68 kDa, 45 kDa, 27 kDa, 3 8 kDa, and 15 kDa, respectively); lanes B, C, D, and E: 2 ug of 20 kDa mPEG-O^-pbefiylacetaldehyde-modifted IFN-p1-1 a removed for assay at day 0,2,5, and 7, respectively FIGS. 7A-B show the antiviral activity of various PEGylaled human IFN-fJ-l a samples .ts a function of protein concentration: FIG 7A; unmodified II-'N-fMa (O >, 20 kDa mPEG-O- 2-racthyrpropiOfia|dchyde-modificd £FN-ß-la (OK 20 kDa mPE(J-O-/j-melhy]phenyl-O-2- methylpropionaldehycfc-modtficd IFN-O-la (A), and20 kDa mPEG-O-M-mcthylpbenyl-O^- raclhylprapionaldehydc-modificd IFN-O-la (o). FIG 7B; umrtodified IFN-ß-Ia (0), 20 kDa mPEG-O-ß-pheny1acetaldehyde-modified IFN-ß-Ia {□), 20 kDa mPEG-O-ß-phenylpropronaldehylde-niodified IFN-ß-Ia {), and 20 kDa mPEG-O-m-phenylacetakicbydc- modified IFN-ß-Ia (o) FIGS. 8 A-B arc graphs depicting the pharmacokinetics of uamodified and various PEGylated human IFN-iM a sample*: FIG. 8A Unmodified IFN-ß-Ia (upper panel) and IFN-P-la mndifiV d with 20 kDa tnPEG-O2«mefty1propionaldehyde {lower panel), FIG, SB' 1FN-0-1 a. modified with 20 kDa niPEG-O-/^jnethylphcnyl^-2'»nc FIG. 10 is a bar graph comparing a single administration or 20 kDa. mPEG-O-2-ra«mylpropiotialdcbyde-rBi>dificd [f N-fMa, with dairy wlnntustration of unmodified IFN-fM a at reduem$ the number of radially-oriented neovcescls in rna'nu mice carry mg SK-MEL-1 human malignant melanoma cells: treatment with vehicle udrtrol once on day 1 only (bar AX treatment with I Mli (5 nfcr of unmodifwd BFN-ß-la daily on days 1-9 inclusive (bar B); treatment with 1 MU {10 Mg) of 20 kDa mreG-2-mcmytpropioflaldcfaydc-iriodified IFN-fMa. once on day 1 only (bar C I; and treatment with vehicle control daily on days 1-9 inclusive (barD). DLTAILFD DESCRIPTION Oh THE INVENTION The invention is directed to compounds and methods useful in the treatment of various diseases and disorders As explained in detail bekw, suth diseases and disorders include, in particular, those which are susceptible to treatment with interferon therapy, including hot not limited to viral infections sjieh as hepatitis infections and autoimmune diseases such as multiple sclerous. The compounds of the invention include novel, activated polyaftylcnc glycol compounds, according to i'ounula I (Formula Removed) where P is a water soluble polymer such as a polyalkylenc glycol polymer. A non-limitmg list of such polymeis include other polyalkylene oxide homopolymcrs such as polypropylene glycols, polyoxyethylenated polyols, copolymers thereof and block copolymers thereof Other examples of suitable water-soluble and non-peptidic polymer backbones include poly{oxyethyIated polyol), poly(o?efmic alcohol), poly(vinylpyrrolidone), poly{hydmxypropylmethftcrylamide), poly(a-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazohne, poly(N-acTyloyImorpholine) and copolymers, terpolymers, and mixtures thereof In one embodiment, the polymer backbone is polyethylene glycol) or monomethoxy polyethylene glycol (mPEG) having an average molecular weight from about 200 Da to about 400,000 Da. It should be understood that other related polymers are also suitable for use in the practice of this invention and that the use of the term PEG or polyethylene glycol) is intended to be inclusive and not exclusive in this respect The term PEG includes poly(etbylene glycol) in any of its forms, including alkoxy PEG, difuncfional PEG, multi-armed PEG, forked PEG, branched PEG, pendent PEG, or PEG with degradable linkages therein Tn the class of compounds represented by Formula I, there are between zero and five methylene groups between Y and the Z-containing carbon (e g, n is zero or an integer from one to five) and m is zero or one, e.g., Y is present or absent X and Y arc, independently, O, S, CO, COj, COS, SO, SO2, CONR', SO2NR\ or NR\ In some embodiments, X and Y are oxygen Q is a C3 to Cs saturated or unsaturated cyclic alkyl or cyclic heteroalkyl (including fused bicyclic and bridged bicyclic ring structures), a substituted or unsubstituted aryl or heteroaryl group, or a substituted or unsubstituted alkaryl wherein the alkyl is a C| to C20 saturated or unsaturated alkyl or heteroalkaryl group. The substituents can be halogen, hydroxy], carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphmate, amino, amido, amidine, imine, cyano, rotm, azido, siilfhydryl, sulfate, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatn; moiety, lmmo, sulfamoyl, sulfonate, silyl, ether, OT alkylthio. The Z substituent is hydrogen, a straight- or branched-charn, saturated or unsaturated C] to C2f> alkyl or heteroalkyl group, C3 to Cs saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl gioup or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C211 saturated 01 unsaturated alkyl or heceioalkaryl group The substttuents can be halogen, hydroxyl. carbonyl, caiboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioforniate, alkoxyl, phosphoryl, phosphonate, phosphmate. amino, amido, amidme. lmme, cyano, nitro, azido, sulfliydryl, sulfate, sulfonate, sulfamoyl, suJionamido, sulfony], heterocyclyh aralkyl, aromatic moiery, heteroaromatic moiety, lmino. sulfamoyl, sulfonate, silyl, ether, or alkylthio When X or Y is NR'. R' can be hydrogen, a straight- or branched-cham, saturated or unsaturated C1 to C20alkyl or heteroalkyl group, a C3 to C? saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl, wherein the alkyl is a C\ to Go saturated or unsaturated alkyl or heteroalkaryl group. The substituents can be halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioforniate, alkoxyl, phosphoryl, phosphonate, phosphmate, ammo, amido, amidine, mime, cyano, nitro, azido, sulfliydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, sulfamoyl, sulfonate, silyl, ether, or alkylthio R is a reactive functional group, i.e., an activating moiety capable of reacting to form a linkage or a bond between the compound of Formula I and a biologically-active compound or precursor thereof. Thus, R represents the "activating group" of the activated polyalkylene glycol compounds (PGCs) represented by Formala 1 R can be, for example, a carboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, aery Ian ude, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succinimidyl, isocyanate, isotmoiyanate, dithiopyridinc, vmylpyndme, iodoacetamide, epoxide, hydroxysucciniimdyl. azole, maleimide, sulfime, allyl, vmylsulfonc, tresyl. sulfo-N-snccininndyl. dione, mesyl, tosyl, or glyoxal In particular embodiments, R is an aldehyde hydrate. Specific examples of R in the literature include N-succmrmidyl carbonate (see e g., U S. Patent Nos 5,281,698,5,468,478), amine (sec e g, Buckniann et al Makromol Chem. 182.1379 (1981), Zaphpsky et a!. Eur Polym J 19 1177 (1983)), hydrazide {See, eg, Andresze^ al. Makromol. Chem. 179-301 (1978)), succinimidyl propionate and succinimidyl butanoate (see, e g Olson et al in Polv (ethylene glycol) Chemistry & Biological Applications, pp 170-181, Harris & Zaphpsky Eds., ACS, Washington, DC, 1997, sec also U.S. Patent No 5,672,662), succinimidyl succinate (See e.g., Abuchowski et al Cancer Btochem. Biophys. 1.115 (1984) and Joppich et al Macrolol. Chem 180 13S1(1979), succinimidyl ester (see, eg, U.S. Patent No 4,670,417), benzotnazole carbonate {see, e g, U S Patent No 5 5,650,234), glycidyl ether {see, eg., Pifha ef at Eur. J. Biochem 94.11(1979), Ellingef a/., 5«?fec/r Appl Biochem 13 354 (1991), oxycarbonylimidazole [see, eg Beauchamp, et al, Anal. Biochem HI 25 (1983). Tondelli etal J Controlled Release 1 251 (1985)), p-nitrophenyl carbonate {see. e g,, Veronese, et al. Appl Biochem. Biotech., 11 141 (1985); and Sartore et al, Appl. Biochem. Biotech.. 27-45 10 (1991)), aldehyde {see, e.g, Hams et al J Pofym. Sci Chem. Ed 22:341 (1984), U S. Patent No 5,824,784,U.S. Patent 5,252,714), malemhde {see, eg., Goodson et al Bio/Technology 8:343 (1990), Romam et al in Chemistry of Peptides and Proteins 2'29 (1984)), and Kogan, Synthetic Comm 22:2417 (1992)). orthopyridyl-disulfide {see, e.g., Woghiren, etal. Bioconj Chem 4.314 (1993)}, acrylol {see, e.g , Sawhney 15 etal., Macromolecules, 26:581 (1993)). vmylsulfone (see. e.g, U.S PatentNo. 5,900,461). In addition, two molecules of the polymei of this invention can also be linked to the amino acid lysine to form a di-substituted lysine, which ran then be further activated with N-hydroxysuccvnimide to form an active N-succmimidyl moiety {i>ec, e g, U.S Patent No 5,932,462) The terms "functional group", "active moiety"', "active group", "activating group", "activating moiety", "reactive site", "chemically-reactive group" and' chemically-reactive moiety" are used in the art and herein to refer to distinct, definable portions or units of a molecule Die terms are somewhat synonymous in the chemical arts and are used herein to indicate the portions of molecules having a characteristic chemical activity dnd which are typically reactive with other molecules. The term "active," when used in conjunction with functional groups, is intended to include those functionai groups that react readily with electrophihc or nucleophihc groups on other molecules, in contrast to those groups that require strong catalysts or highly impractical reaction conditions m order to react For example, as would be understood in the art, the term "active ester" would include those esters that react readily with nucleophihc groups such as amines. Typically, an active ester will react with an amine m aqueous medium in a matter of minutes, whereas certain esters, such as methyl or ethyl esters, require a strong catalyst in order to react with a nucleophihc group. In the compounds of the invention as defined above, the functional group R becomes a linking moiety, R*, after it has reacted with a biologically-active molecule to form a linkage or bond between the activated polyalkylcnc glycol compound (PGC) and the biologically-active compound Thus, B is a biologically-active compound after conjugation to the PGC and R* is a moiety formed by the reaction of R on the activated PGC with one or more reactive functionai groups on the biologically-active compound, B, such (hat a single covalcnt attachment results between the PGC and biologically-active compound In a preferred embodiment, RMs a moiety formed by the reaction of R on the activated PGC with a single reactive functional group on the biologically-active compound, such that a covalent attachment results between the activated polyalkylene glycol compound (PGC) and the biologically-active compound The biologically-active compound or precursor thereof (B) is preferably not adversely affected by the presence of the PGC Additionally, B either naturally has a functional group which is able to react with and form a linkage with ihe activated PGC, or is modified tu contain such a reactive group As used herein, a precursor of B is an inactive or less active form of B that changes to the active or more active form, respectively, upon contact vvith physiological conditions, e.g., administration to a subject Such changes can be conformational or structural changes, including, but not limited to, changing from a protected form to a non-protected form of B. As used herein, such change does not include release of the conjugated PGCs ot this invention. As would be understood in the art. the term 'protected' refers to the presence of a protecting group or moiety that prevents reaction oi the chemically-reactive functional group under certain leaction conditions. The protecting gioup will vary depending on the type of chemically-reactive group being protected For example, if the chemically-reactive group is an amine or a hydrazide, the protecting group can be selected from the group of tert-butyloxycarbonyl (t-Boc) and 9-fluorenylmethoxycarbonyl (Fmoc). If the chemically-reactive group is a thiol, the protecting group can be orthopyndyldisulfide. If the chemically-reactive group is a carboxylic acid, such as butenoic or propionic acid, or a hydroxyl group, the protecting group can be benzyl or an alkyl group such as methyl or ethyl Odier protecting groups known in the art may also be used in the invention The terms "linking moiety"', "linkage" or "linker" are used herein to refer to moieties or bonds that are formed as the result of a chemical reaction and typically are covalent linkages. Thus, the linkage represented by bond R*-B m the above formulae results from the reaction between an activated moiety, R, on the PGC with a biologically-active compound, i.e, B'. R* is the linking moiety formed from R upon reaction with B', and B is the biologically-active compound as conjugated to the PGC by reaction of a functional group on B" with R. As used herein, the term "biologically-active compound" refers to those compounds that exhibit one or more biological responses or actions when administered to a subject and contain teactive groups that contain reactive moieties that are capable of reacting with and conjugating to at least one activated PGC of the invention fhe term "biologically-active molecule", "biologically-active moiety" or "biologically-active agent" when used herein means any substance which can affect any physical or biochemical properties of any subject, including but not limited to viruses, bactena, fungi', plants, animals, and humans In particular, as used herein, biologically-active molecules include any substance intended for diagnosis, cure, mitigation, treatment, or prevention of disease in humans or other animals, or to otherwise enhance physical or mental well-being of humans or animals. Examples of biologically-active molecules include, but are not limited to, peptides, peptide analogs, proteins, enzymes, small molecules, dyes, lipids, nucleosides, oligonucleotides, analogs of oligonucleotides, sugars, oligosaccharides, cells, viruses, liposomes, microparticles, surfaces and micelles. Classes of biologically-active agents that are suitable for use with the invention include, but are not limited to, chemokincs, lymphokmes, antibodies, soluble receptors, anti-tumor agents, anti-anxiety agents, hormones, growth factors, antibiotics, fungicides, fungistatic agents, anti-viral agents, steroidal agents, antimicrobial agents, germicidal agents, antipyretic agents, antidiabetic agents, bnmchodilators, antidiarrheal agents, coronary dilation agents, glycosides, spasmolytics, antihypertensive agents, antidepressants, antianxiety agents, other psychotherapeutic agents, corticosteroids, analgesics, contraceptives, nonsteroidal antiinflammatory drugs, blood glucose lowering agents, cholesterol lowering agents, anticonvulsant agents, other anliepileptic agents, immunomodulators, anticholinergics, sympatholytics, sympathomimetics, vasodilatory agents, anticoagulants, antiarrhythmics, prostaglandins having various pharmacologic activities, diuretics, sleep aids, anahistammic agents, antmeoplastic agents, oncolytic agents, antiandrogens, antimalarial agents, antileprosy agents, and various other types of drugs. See Goodman and Oilman's The Basis of Therapeutics (Ninth Edition, Pergamon Press, Inc, USA, 1996) and The Merck Index (Thirteenth Edition, Merck & Co, Inc., USA, 2001), each of which is incorporated herein by reference Biologically-active compounds include any compound that exhibits a biological response m its present form, or any compound that exhibits a biological response as a result of a chemKal conversion of its structure from its present form. For example, biologically-active compounds will include any compound that contains a protective group that, when cleaved, results in a compound that exhibits a biological response Such cleavage can be the result, for example, of an in vivo reaction of the compound with endogenous enzymes or a pre-admmislratjon reaction of the compound, including its reaction with the activated PGCs of this invention As a further example, biologically-active compounds will also include any compound which undergoes a stereotransformation, in vivo or ex vivo, to form a compound that exhibits a biological response or action. Biologically-active compounds typically contain several reactive sites at which covalent attachment of the activated PGC is feasible. For example, amine groups can undergo acylatrons, sulfhydryl groups can undergo addition reactions and alkylations, carbonyl and carboxyl groups can undergo acylations, and aldehyde and hydroxyl groups can undergo animation and reductive animation. One or more of these reactions can be used in the preparation of the polyalkylene glycol-modified biologically-active compounds of the invention. In addition, biologically-active compounds can be modified to form reactive moieties on the compound that facilitate such reactions and the resultant conjugation to the activated PGC Those of ordinary skill will recognize numerous reaction mechanisms available to facilitate conjugation of the activated PGC to a biologically-active compound. For example, when the activating moiety, R, is a hydrazide group, it can be covalendy coupled to sulfhydryl, sugar, and carbonyl moieties on the biologically-active compounds (after these moieties undergo oxidation to produce aldehydes). The reaction of hydrazide activating moieties (R) with aldehydes on biologically-active compounds (B') creates a hydrazone linkage (R*-B). When R is a malerrnide group, it can be reacted with a sulfhydryl group to form a stable thioether linkage. If sulfhydryls are not present on the biologically-activc compound, they may be created through disulfide reduction or through thiolation with 2-iminothiolane or SATA. When R is an imidoester it will react with primary amines on B" to form an imidoamide linkage. Imidoester conjugation is usually performed between pH 8.5-9.0. When connecting the activated PGCs to biologically-activc protems, lmidoesters provide an advantage over other R groups since they do not affect the overall charge of the protein They carry a positive charge at physiological pH, as do the primary amines they replace. Imidoester reactions are carried out between 0 °C and room temperature (e.g., at 4 °C), or at elevated temperatures under anhydrous conditions When R is an NHS-ester, its principal target is primary amines Accessible c-amine groups, for example those present on the jV-termini of peptides and proteins, react with NHS-esters to form a covalent amide bond In some embodiments, R*-B is a hydrolytically-stable linkage. A hydroiytically stable linkage means that the linkage is substantially stable in water and does not react with water at useful pHs, e g, the linkage is stable under physiological conditions for an extended period of time, perhaps even indefinitely In other embodiments, R*-B is a hydrolytically-unstable or degradable linkage A hydrolytically-unstable linkage means that the linkage is degradable in water or in aqueous solutions, including tor example, blood Enzyinatically-unstable or degradable hnkages also means that the linkage can be degraded by one or more enzymes. As understood in the art, polyalkylene and related polymers may include degradable linkages in the polymer backbone or in the linker group between the polymer backbone and one or more of the terminal functional groups of the PGC molecule For example, ester hnkages formed by the reaction of, e.g., PGC carboxylic acids or activated PGC carboxylic acids with alcohol groups on a biologically-active compound generally hydrolyze under physiological conditions to release the agent Other hydrolyticalry-degradabJe linkages iuclude carbonate linkages, mime linkages resulted from reaction of an amine and an aldehyde (See. e.g, Ouchi at al, Polymer Preprints, 3S(l).582-3 {1997)); phosphate ester linkages formed by reacting an alcohol with a phosphate group; acetal linkages that are the reaction product of an aldehyde and an alcohol; orthoestcr linkages that are the reaction product of a formate and an alcohol; peptide linkages formed by an amine group, e g , at an end oi a the PGC, and a carboxyl group of a peptide, and oligonucleohde linkages formed by a phosphoramidite group, eg., at the end of a polymer, and a 5' hydroxyl group of an oligonucleotide. The polyalkylene glycol, P, can be polyethylene glycol, having the structure of Formula II (Formula Removed) wherem a is an integer from 4 to 10,000 and E is hydrogen oi a straight- or branched-chain C1 Lo C20 alkyl group, a detectable label, or a moiety suitable for forming a bond between the compound of Formula I and a biologically-active compound or precursor thereof. Thus, when E is a moiety suitable for forming a bond between the compound of Formula I and a biologically-actrve compound or precmsor thereof, E can be a carboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstmited amine, protected amine, hydrazide, protected hydrazidc, succinimidyl, lsocyanate, isothiocyanate, dithiopyridine, vinylpyridine, lodoacetarrride. epoxide, hydroxy succinimidyl, azole. maleimidc, sulfonc, ally], vinylsulfone, tresyl, sulfb-N-succinimidyl, dione, mesyl. tosyl, or glyoxal It is to be understood that R should be compatible with R so that reaction between E and R does not occur B> "detectable label"" is meant any label capable of detection. Non-limiting examples include radioactive isotopes, fluorescent moieties, phosphorescent moieties, chemiluminescent moieties, and quantum dots Other detectable labels include biotin, cysteine, histidine, haemagglutwin, myc or flag tagb. In some embodiments. E has the structure according to Formula III or Formula IV■ (Formula Removed) Each 0, X, Y, Z, m, and n are as defined above, and each W is, independently, hydrogen or a G to C7 alkyl In this class of compounds, R" is a moiety buitable for forming a bond between the compound of Formula HI and a biologically-active compound or precursor thereof: andR,,J is a moiety suitable for forming a bond between the compound of Formula IV and a biologically-active compound or precursor thereof. R" and R*'" can be of carboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl. acrylate, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted oi unsubstituted amine, protected amine, hydrazide, protected hydrazide, succmimidyl, isocyanate, isothiocyanate, dithiopyridine, vinylpyridinc, lodoacctamide, epoxide, hydroxysuccinimidyl, azole, nidleirnide, sulfone, allyl, vinylsulfone, tresyl, sullo-N-succmiraidyl, dione, mesyl, tosyl, oi glyoxal. It is to be understood thatR" and R"' should be compatible with R so that reaction with R does not occur As used herein, R" and R'", upon conjugation to a biologically-aetrve compound or precursor thereof, form linking moieties as defined above. Thus, R** is a linking moiety formed by the reaction of the R" orR'" group on the activated PGC with a reactive functional group on the biologically-active compound, such that a covalent attachment results between the PGC and the biologically-active compound R and R' or R"' can be the same moiety or different moieties, and the biologically-active compound bound To each can be the same or diffeient As used herein, the term "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-cham alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e g , C,-CJ0 for straight chain, C3-C30 for branched chain), and more preferably 20 or fewer Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6, OT 7 carbons in the nng structure Moreover, the term "alkyl" (or "lower alkyl") is intended to include both "unsubstituted alkyls" and 'substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphonate, a phosphmate, an amino, an amido, an amidine, an inune, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a s'ulfamoyl, a sulfonamido, a sulfonyL a heterocyclyl, an aralkyl or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, miino, amido, phosphoryl (including phosphonate and phosphmate), sulfonyl (including sulfate, sulfonamido. sulfarnoyl, and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, amraoalkyls, carbonyl-substituted alkyls,-CF3, -CN, and the like The term "aralkyl", as used herein, refers to an alkyl group substituted with an aryl group (e.g.. an aromatic or heteroaromatic group) Exemplary aralkyl groups include, but are not limited to, benzyl and more generally (CH2>nPh, where Ph is phenyl or substituted phenyl, and n is 1,2, or 3 The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous m length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms m its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Preferred alkyl groups are lower alkyls. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl. The term "aryl" as used herein includes 5-, 6-, and 7-membcred single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, (fuophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazme, pyndpzine and pynmidine, and the like. Those aryl groups having heteroatoms in the nng structure may alsi be referred to as "aryl heterocycles" or "heteroaromatics " The aromatic ring can be substitute at one or more ring positions with such substituents as described above, for example, halogen. azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, mtro, sulfhydryl, immo, amido, phosphonate, phosphmate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3 -CN, or the like The term Llary!" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, and/or heterocyclyls. The terms ortho, meta and para apply to 1,2-, 1,3-. and 1,4-disubstituted benzenes, respectively For example, the names 1,2-dimethylbenzene and o/tfto-dimethylbenzene are synonymous The terms "heterocyclyl" or "heterocyclic group" refer to 3- to 10-membered nng structures, more preferably 3- to 7-membered rings, whose nng structures include one to four heteroatoms. Heterocycles can also be polycycles Heterocyclyl groups include, for example thiophene, thiamhrene, iuran, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyndine, pyrazine, pynmidine, pyndazme indolizine, isoindole, indole, mdazole, punne, qumohzine, isoqumoline, quinoline, phthalazim naphthyridme, quinoxahne, qumazoline, cmnolme, ptendine, carbazole, carboline, phenanthndme, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazme fiirazan, phenoxazme, pyrrolidine, oxolane, thiolane, oxazole, pipendine, piperazme, morphohne, lactones, lactams such as azetidinones and pynolidmones, sultams, sultones, and the like. The heterocychc nng can be substituted at one or more positions with substituents as described above, such as, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, mtro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic heteroaromatic moiety, -CF3, -CN, or the like. [Tie term "carbocycle", as used herein, refers to an aromatic or non-aromatic nng in which each atom of the ring is carbon Heterocycles and carbocycles include fused bicyclic and bndged bicychc ring structures. As used herein, the term "nitro" means -NO2, the term "halogen" designates -F, -CI, -Br or -I, the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH, and the term "sulfonyl" means -SCb- The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, e g, a moiety that can be represented by the general formula- (Formula Removed) wherein RQ, R]Q and K \ty each independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)m-R-8> or Ry and Rjrj taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; Rg represents an ary], a cycloalkyl, a cycloalkenyl, a heterocycle or a polycyele. and m is zero or an integer in the range of 1 to 8 The term "alkylamme" as used herein means an amine group, as defined above, havmg a substituted or unsubstituted alkyl attached thereto, i.e., at least one of Ro, and R] Q IS an alkyl group The term "acylamino" is art-recognized and refers to a moiety that can be represented by the general formula-0 - N—"—R'a R9 wherein R9 ib as defined above, and R'j j represents a hydrogen, an alkyl, an alkenyl or -(CH2)m"^8' where m and R^ are as defined above The term "amido" is art-recogruzed as an amino-substituted carbonyl and includes a moiety that uan be represented by the general formula o (Formula Removed) wherein R9, RJO are as defined above Preferred embodiments of the amide will not include lmides which may be unstable. The term "amidine" is art-recognized as a gioup that can be represented by the.general formula. (Formula Removed) wherein R9, RIQ are as defined above J he term "guanidmc' is art-recognized as a group that can be represented by the general formula- (Formula Removed) wherein R9. R[Q arc as defined above The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In preferred embodiments, the "alkylthio" moiety is represented by one of-S-alkyf -S-alkenyl, -S-alkynyl, and -S-(CH2)m"'^8> WQerein m and Rg are defined above. Representative alkylthio groups include methylthio, ethyllhio, and the like. The term "carbonyl" is art-recognized and includes moieties that can be represented by the general formula1 (Formula Removed) whereui X is a bond or represents an uxygen or a sulfur, and R\ \ represents a hydrogen, an alkyl, an alkenyl, -{CH2)m-R8 or a phamiaceutcally-acccptable salt, R'j ] represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-Rg, where m and Rg are as defined above. Where X is an oxygen and R( 1 orR'j j is not hydrogen, the formula represents an "ester". Where X is an oxygen, and Rj \ is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R( ] is a hydrogen, the formula represents a "carboxyhc acid" Where X is an oxygen, and R'\ \ is hydrogen, the formula represents a "formate" In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiolcarbonyl" group. Where X is a sulfiir and Rj \ or R'j j is not hydrogen, the formula represents a "thioester." Where X is a sulfur and R} j is hydrogen, the formula represents J "thiocarboxyiic acid " Where X is a sulfur and R'i \ is hydrogen, the formula represents a "thioforraate." On the other hand, where X is a bond, and Ri j is not hydrogen, the above formula represents a "ketone" group Where X is a bond, and R\ ] is hydrogen, the above formula represents an "aldehyde" group The terms "alkoxyl" or "alkoxy" as used herein refers to an alkyl group, is defined above, having an oxygen radical attached thereto Representative alkoxyl groups include mcthoxy, ethoxy, pmpyloxy, tert-butoxy, and the like. An "ether" is two hydrocarbons covalently linked by an oxygen Accordingly, the substituent of an allcyl that renders that alkyl an ether is or resembles an slkoxyl, such as can be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(CH?)m-R8' where m and Rg are described above The term "sulfonate" is art-recognized and include;, a moiety that can be represented by the general formula (Formula Removed) in which R41 is an electron pair, hydrogen, alkyl cjcloalkyl, or aryl The term "sulfate" is art Tecogruzcd and includes a moiety that can be represented by the general formula. (Formula Removed) in which K4] is as defined above The term "sulfonamide" is art recognized and includes a moiety that can be represented by the general formula (Formula Removed) in which R9 and R'j j are as defined above The term "sulfamoyl" is art-recognized and includes a moiety that can be represented by the general formula (Formula Removed) m which R9 and K\Q are as defined above. The term "sulfonyl". as used herein, refers to a moiety that can be represented by the general formula' (Formula Removed) in which R44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl The term "sulfoxido" as used herein, refers to a moiety that can be represented by the general formula: (Formula Removed) in which R44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e g, which does not spontaneously undergo transformation such as by rearrangement, cyclizahon, elimination, etc As used herein, the term "substituted" is contemplated to include all permissible substituents of orgamc compounds In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromahc substituents of organic compounds Illustrative substituents include, for example, those described herein above The permissible substituents can be one or more and the same or different for appropriate orgamc compounds For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of orgamc compounds A comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears m the first issue of each volume of the Journal of Organic Chemistry, this list is typically presented in a table entitled Standard List of Abbreviations The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill m the art are hereby incorporated by reference In some embodiments, the compounds of the invention have the structure according to Formula V (Formula Removed) X, Y, m, n, Z, and R' are as defined above, and R is an activating moiety as defined above, suitable for forming a bond between the compound of Formula V and a biologicalry-achve compound or precursor In particular embodiments, R is an aldehyde hydrate P is as defined above, and can be represented by Formula LI (Formula Removed) where E is as described above, and m some embodiments, can be represented by Formula III or IV Ti and Ti are, independently, absent, or a straight- or branched-chain, saturated or unsaturated Q to C20 alkyl or heteroalkyi group, a C1 to Cg saturated or unsaturated cyclic alkyl or cyclic heteroalkyi, a substituted or unsubstituted aryl or heteroaryl group, or a substituted or unsubstituted alkaryl wherein the alkyl is a C\ to CM saturated or unsaturated alkyl or heteroalkaryl group The substitucnts can be halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphmate, amino, amido, amidine, imine, cyano, nitro, aado, sulfhydryl, sulfate, sulfonate, sulfamoyl, .sulfonamide, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatjc moiety, immo, silyl, ether, or alkylthio When d is zero, there are no additional substituents (L) on the aromatic ring. When d is an integer from I to 4, the substituents (L) can be a straight- or branched-chain, saturated or unsaturated C1 to C20 alkyl or heteroalkyi group, C3 to Cg saturated or unsaturated cyclic alkyl or cyclic heteroalkyi, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherem the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group The substituents can be halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioforrrmtc, alkoxyl, phosphoryl, phosphorate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyefyj, aralkyl, aromatic moiety, heteroaromatic moiety, rmmo, silyl, ether, or alkylthio When R is an aldehyde, the compounds fall within those represented by Formula VI: (Formula Removed) where all other variables are as defined above Foi example, when X and Y are oxygen and R is an aldehyde, the compounds of the invention are represented by compound J (Formula Removed) where the T1 and T2 substitaents can be in the ortho, meta, or paia arrangement Where theTi and T2 substiruents are straight-chain aikyl groups, and d is zero, the compounds are represented by Formula IX. (Formula Removed) where each u is independently zero or an integer from one to five and all other variables are as defined above. In particular embodiments, Z is hydrogen or methyl Particular classes of compounds falling within Formula IX can be represented by Formulae VII and VIII' (Formula Removed) Some representative activated poJyaJkylenc glycol compounds include the following, where the polyallcylene glycol polymer is PEG or mPEG (Table Removed) In some embodiments, the compounds of lie invention are represented by Formula X (Formula Removed) where, as above, n is zero or an integer from one to five, and X is 0, S, CO, CO;, COS, SO, SOj, CONR', SC^NR', or NR' When X is NR", R' can be hydrogen, a straight- or branched-eham, saturated or unsaturated C| to Qo alkyl or heteroalky) group, G to C.% saturated or unsaturated cyclic alkyl or cyclic hcteroalkyl, a substituted or unsubstituted aryl nr heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C\ to Cy, saturated or unsaturated alkyl or hcteroalkaryl group, wherein the substitucnts are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylatc, ester, fonnyl, acyl. thiocarbonyl, thioester, thioatetate. thioformate, aflcoxyl, phosphoryl, phosphonatc, phosphinate, ammo, amido, amidine, rmine, cyano, nitro, azido, sulrhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, oialkyl, aromahc moiety, heteroaiomatic moiety, irmno, silyl, ether, or alkylthio L can be a straight- or branched-chain, satuialed or unsaturated C (to Q>o alkyl or heteroalkyl group, C3 to C& saturated or unsaturated cyclic alkyl or cyclic heteroalkyl. a substituted or unsubstirutcd aryl orhetertwryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C| to CM saturated or unsaturated alkyl or heteroalkaryl group. When present, the substituenls can be halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioebler, thioaceiate, thioformatc, alkoxy), pnosphoryl, phosphonate, phosphmate, amino, anudo, amidine, imine, cyano, nitru, azido. sulfhydryl, sulfate, siilfomte, sulfamoyl sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, or alkylthio. As defined above, R is an activating moiety suitable for forming a bond between the compound of Formula X and a biologically-actrve compound or precursor thereof In some embodiments, R is an aldehyde hydrate. P is a polyalkylene glycol polymer as defined above, and can be represented by Formula II (Formula Removed) where E and a are as described above, and in some embodiments, can be represented by Formula III or IV. In some embodiments, E is methyl, and. therefore, P is rnPEG When R is an aldehyde and X is oxygen, the compounds fall within the structure according to Formula XI' (Formula Removed) where P, Z and n are as defined for Formula X When P is niPEG, the compounds are described by Formula XII (Formula Removed) and when n is one and Z is methyl, the compound is represented by Formula XIII (Formula Removed) wherein a is an integer from 4 to 10,000 Examples of synthetic pathways for making compounds according to the invention are set forth in the Examples below The invention also includes compositions of the activated polyalkylene glycol compounds (PGCs) of the invention and one or more biologicalfy-active compounds As described above, biologically-active compounds are those compounds that exhibit a biological response or action when administered to a subject Unconjugated biologically-active compounds may be administered to a subject in addition to the compounds of the invention. Additionally, biologically-active compounds may contain reactive groups that arc capable of reacting with and conjugating to at least one activated PGC of the invention The invention also includes conjugates of the novel PGCs wrthbiologically-active compounds. In one embodiment, the conjugates arc formed from a compound of Formula I and abiologically-actrve compound (B) and are described according to Formula XIV. (Formula Removed) As above, ni is zero or one so that Y is present or absent, n is zeio or an integer from one to five, and X and Y are independently 0, S, CO, CO:, COS, SO, SO2, CONR', SOjNR', orNR- Q is a C3 to C$ saturated or unsaturated cyclic alkyl or cyclic heteroalkyl (including fused bicyclic and bridged hicychc ring structures), a substituted or unsubstituted aryl or heteroaryl group, or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to Cjo saturated or unsaturated alkyl or heteroalkaryl group When presemt, the substituents can be halogen, hydroxy], caibonyl, carboiykte, ester, formyl, acyl, thocarbmyl ihtoester, thioacetate. thioformate, alkoxyl, phosphoryl, phosphonate, phosphmale, amino, amido, amidine, imine, cyano, rutro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyi, araikyl, aromatic moiety, heteroaromatic moiety, umnc, silji, ether, or alkylttoo. Each R' and Z is independently hydrogen, a straight- or branched-chain, saturated or unsaturated C| to C20 alkyl or heteroalkyl group, C3 to Q saturated or unsaturated cyclic alky] or cyclic heteroalkyl, a substituted or unsubsliluted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherem the sitbstituents are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, forrrrvl, acyl, thiocarbonyi, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phospliinate, amino, araido, arnidme, rmine, cyano, nitio, azido, snlfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyi. araikyl, aromatic moiely, heteroaromatic moiety, miino, silyl, ether, and alkyrthio, R* is a linking moiety formed from the reaction of R with a corresponding functional group on the biologically-active compound, B, as described above for example, R* is formed from the reaction of a moiety such as a carbovyhc acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrvlamide, substituted or unsubstituted thiol, halogen, substituted OT unsubstituted amine, protected amine, hydrazide, protected hydrazide, succuiimidyl, isocyanate, isothiixryanate, dithiopyndine. vmylpyndine, lodoacetamide, epoxide, hydroxysuccirumidyl, azole, maleirrude, sulfone, altyl, vinylsulfbne, tresyl, sulfo-N-succinimidyl, dione. mesyl, tosyl, or glyoxal Ainctionality with a biologically-active compound or precursor thereof P is a polyalkyiene glycol polymer 33 defined above, and can be represented by formula II (Formula Removed) where E is hydrogen, a straight- or brancbed-chaui C1 to C20 alkyl group (e g, methyl), a detectable label, or a moiety suitable for forming a bond between the compound of Formula XIV and a biologically-active compound or precursor thereof As above, a is an integer from 4 to 10,000 Where E is a detectable label, the label can be, for example, a radioactive isotope, a fluorescent moiety, a phosphorescent moiety, a cherrulummesoeiil moiety, or a quantum dot. When E is a moiety suitable for forming a bond between the compound of Formula XFV and a biologically-active compound or precursor thereof, E tan form a bond to another molecule of the biologically-acnve compound (B) so that the activated polyalkyiene glycol compound is bound at either terminus to a molecule of the same type of bologically-active compound, to produce a dimer of the molecule In some embodiments, b forms a bond to a biologically-active compound other thanB, creating a heierodimer of biologicalry-activc compounds or precursors thereof In other embodiments, Ii forms an additional bond to the biologically-active compound, B, such thai both E and R are bound through different functional groups of the same molecule ot the biologically-active compound or precursor thereof When E is capable of forming a bond to a biologically-active molecule or precursor thereof, E can be the same as or different from R and is chosen from carboxyhc acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succinirmdyl, lsocyanate, isothiocyanate, dithiopyridme, vnryipyridine, lodoacetamide, epoxide, hydroxysuccmimidyl. azole, maleirmde, sulfone, allyl, vinylsulfone, tresyl, sulfo-N-succinxmidyl, dione, mesyl, tosyl, and glyoxal moieties When b is capable of forming a bond to a biologically-active molecule or precursor thereof, E can have the structure according to Formula III or Furmula IV (Formula Removed) where each Q, X, Y, Z, m, and n are, independently, as defined above, each W is, independently, hydrogen or a O to C7 alkyl, R" is a moiety suitable for forming a bond between the compound of Formula HI and a biologically-active compound or precursor thereof, and R'"' is a moiety suitable for forming a bond between the compound of Formula IV and a biologically-active compound or precursor thereof R" and R'1' are, independently chosen from carboxyhc acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate., acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succmimidyl, isocyanate. isothiocyanate, ditliiopyndine, vinylpyndine, lodoacetamide, epoxide, hydroxysucciiiirnidyl, azole, maleimide, sulfone, allyl, vinylsulfone, tresyl, sulfo-N-succinimidyl, dione, mesyl, tosyl, and glyoxal moieties When Q m Formula XIV is a substituted or unsubstituted alkaryl, the conjugate is formed from an activated poryalkylene glycol of Formula V and a biologically-active molecule (R), and is described according to Formula XV: (Formula Removed) (L)d where Ti and T^ are, independently, absent, or a straight- or branched-chain, saturated or unsaturated C1 to C20 alkyl or heteroalk>'l group, a C3 to Cg saturated or unsaturated yyckc alkyl or cyclic heteioalkyl, a substituted or unsubstituted aryl or heteroaryl group, or a substituted or unsubstituted alkaryl wherein the alky] is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group. When present, the substituents can be halogen, hydroxyl, carbonjl, carboxylale, ester, fornryl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phospbonate, phosphinate, amino, amido, amidine, lirune, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, beterocyclyl. aralkyl, aromatic moiety, heteroatomatic moiety, irmno, silyl, ettier, or alkylthio In some embodiments, Ti and T;, if present, dm straight- or branched-chain saturated or unsaturated or C1 to C20 alkyl or heteroalkyt group. d is zero (e g., there are no L substituents on the aromaLic nng) or an integer from 1 to 4. Each L is, when present, a straight- orbranched-cbam, saturated or unsaturated C1 to C20 alkyl orhcteroalkyl group, C3 to Cg saturated or unsaturated cyclic alkyl or cychc heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to (J20 saturated or unsaturated alkyl or heteroalkaryl group The substituents. can be halogen, hydroxyl, carbonyl, carboxylnte, ester, formyl, acyl, thiocarbonyl, thioester, thioacerate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidine. imine, cyano, nitro, azido, sulfhydryl. sulfate, sulfonate, sulfamoyl, salfonanndo, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, or alkylthio. All other variables are as described above, including P, which is a polyalkylene glycol polymer, and can be represented by Formula H (Formula Removed) where E is hydrogen, a straight- or branched-chain C1 to Ci0 alky] group (e.g , methyl), a detectable label, or a moiety suitable for forming a bond between the compound of Formula XV and a biologically-active compound or precursor therenl As above, a is an integer from 4 to 10,000 Where E is a detectable label, the label can be, for example, a radioactive isotope, a fluorescent moiety, a phosphorescent moiety, a chemiluminescent moiety, or a quantum dot. When E is a moiety suitable for forming a bond between the compound of Formula XV, and a biologically-active compound, B, E can form a bond to another molecule of the biologically-active compound (B) so that the activated polyalkylene glycol compound is bound at either terminus to a molecule of the same type of biologically-active compound, to produce a dimer of the molecule. In some embodiments, E forms a bond to a biologically-active compound other than B, creating a heterodrmer of biologically-actrve compounds or precursors thereof In other embodiments, E forms an additional bond to the biologically-active compound, B, such that both E and R are bound through different functional groups of the same molecule of the biologically-active compound or precursor thereof When E is capable of forming a bond to a biologically-active molecule or precursor thereof, E can be the same as or different from R and is chosen from carboxyhc acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succimmidyl, isocyanate, isothiocyanate, dithiopyndine, vinylpyridine, lodoacetonide, epoxide, hydroxysuccimmidyl, azole, maleimide, sulfone, alh/I, vmylsulfone, tresy], sulfo-N-succmimidyl, dione, mesyl, tosyl, and glyoxal moieties. When E can form a bond with a biologically-acti ve compound or precursor thereof, m some embodiments, E can be Formula 111 or Formula IV (Formula Removed) where each Q, X, Y, Z, m, and n are, independently, as defined above, each W is, independently, hydrogen or a Ct to C7 alkyl, R' is a moiety suitable for forming a bond between the compound of Formula III and a biologically-active compound or precursor thereof, and R'"' is a moiety suitable for forming a bond between the compound of Formula IV and a biologitally-achve compound or precursor thereut R" and R'" are, independently chosen from carboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl. acrylate, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amvne, protected amine, hydrazide, protected hydrazide, succmimidyl, ibocyanate, isothiocyanatc, dithiopyndine, vinylpyridme, iodoacetaroide, epoxide, hydroxysuccinimidyl, azole, rnalenrnde, sulfone, allyl, vmylsulfone. tresyl, sulfo-N-sutcinimidyl, dione, mesyl, tosyl, and glyoxal moieties. When bound at both ends to a biologically-active compound or precursor thereof, these bifuncrJonal molecules can be lepresented according to Formula XX or Formula XXI. (Formula Removed) where each X and Y, T, and T;. R' and Z, L, Q, m, n, a, and n are as described above. and each W is, independently, hydrogen or a d to C7 alkyl R* and R** are, independently, linking moieties formed from the reaction of R and R ' w ith a biologically-active compound or precursor thereof, and B and B' are each a biologically-active compound, or precursor thereof, after conjugation with R and R", respectively. In some embodiments. B and B' are the same type of biologically-active compound In other embodiments, B and B' are different biologically-active compounds In still other embodiments, B and B' are the same biologically active molecule. In additional embodiments, R* and R** are the same In other embodiments, R* and R** are different For example, in some embodiments, E can form a bond to another molecule of the biologically-active compound (B = B') so that the activated PGC is bound at either terminus to a molecule of the same type of biologically-active compound, to produce a dimer of the molecule In some embodiments, E forms a bond to a biologically-active compound other than B (B is not B'), creating a heterodrmer of biologically-achve compounds or precursors thereof In other embodiments, E forms an additional bond to the biologically-active compound, B, such that both E (through R" or R'") and R are bound through different functional groups of the same molecule of the biologically-active compound or precursor thereof. In some embodiments, R* or R** is methylene group and B or B' is a bsologically-active molecule containing an ammo group, where the methylene group forms a bond with the amino group on B For example, the amine can be the ammo terminus of a peptide, an amine of an ammo acid side chain of a peptide, or an amine of a gly cosylation substituent of a glycosylated peptide In some embodiments, the peptide is an interferon, such as mterferon-beta, e g., interferon-beta-la In some embodiments, this type of bond is formed by a reductive alkylation reaction Where theT] and T2 substituents of Formula XV are straight-chain alkyl groups, X and Y are oxygen, and d is zero, the conjugates are represented by Formula XIX (Formula Removed) where each u is independently zero or an integer from one to five and all other variables are as defined above In particular embodiments, Z is hydrogen or methyl Particular classes of compounds falling within Formula XV can be represented by Formulae XVII and XVHI formed from the reaction of Formulae VH and VIII, respectively, with a biologically-active compound, or precursor thereof (Formula Removed) where n is zero OT an integer from one to five, P is a polyalkylcne glycol polymer, as described above, Z is hydrogen, a straight- or branched-chafn, saturated or unsaturated C1 to Qoalkyl or heteroalkyl group, R* is a linking moiety as described above, B is a biologically-active molecule. These compounds can be Afunctional or monofunctional, depending on the identity oi E, as described above In some embodiments, R* is a methylene group and B is a biologically-achvc molecule containing an amino group, where the methylene group forms a bond with the amino group w> B For example, the amine scan be the amino terminus of a peptide, an amine of an amino acid side chain of a peptide, or an amine of a glycosylation subsequent of a glycosylated peptide. In some embodiments, the peptide is an interferon, such as mterfeion-beta, e g., mterferon-beta-1 a In some embodiments, this type of bond is formed by a reductive alkylation reaction The conjugates of the invention can also be formed from reaction of compounds according to Formula X with a bwlogically-active compound or precursor thereof, to form conjugates according to Formula XX31. (Formula Removed) where B is a biologically-active molecule, as descnbed above and n is zero or an integer from one to five. X is 0, S. CO. CO2, COS, SO. SO2, CONR\ SONR\ or NR\ when X is NR\ R1 is hydrogen, a straight- or branched-charo, saturated OT unsaturated Q to C20alkyl or heteroalkyl group. C3 to Cf, saturated or unsaturated cyclic alky! or cyclic heteroalkyl, a substituted or unsubstiruted aryl or beteroaryl group or a substituted or unsubstiruted alkaryl wherein the alkyl is a C] lu C20 saturated or unsaturated alkyl or heteroalkaryl group If present, the substituents can be halogen, hydroxyl, carbonyl, carboxylate, esttr, formyi, acyl, (hiocarbonyl, thioester, thioacetate, tfuo form ate, alkoxyl, phosphoryl, phosphonate, phosphuiate. amino, amido, amidme, mime, cyano, mlro, azido, sulfhydry], sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocycly], aralkyl. aromatic moiety, heteioaromatic moiety, immo, silyl. ether, or alkylthio. Z is a straight- or branched-chain, saturated or unsaturated C1 to Chalky? or heteroalkyl group, C3 to Ct saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or urisubstituted aryl or heteroaryl group or a substituted or unsubstiruted alkaryl wherein the alkyl is a C) to Cm saturated or unsaturated alkyl or beteroalkaryt group The substituents can be halogen, hydroxyl. carbonyl, carboxylate, ester, ftmiyl, acyl, thiocaroonyf, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphmate, amino, amido, amidine, imine, cyano, nitro, a/ido, sulfhydryl, sulfate, sulfonate, sulfamuyl, sulfonamido, sulfonyl, heterocyclyl, aralkvl. aromatic moiety, hcteroaromauc moiety, imino, silyl, ether, or alkylthio R* is a linking moiety formed from the reaction of R with a corresponding functional group on the biologically-active compound, B, as descnbed above For example, R* is formed from the reaction of a moiety such as a carboxyhc acid, csteT, aldehyde, aldehyde hydrate, acetal. hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or urisubstituted amine, protected amine, hydrazide, protected hydrazide, succirumidyl, isocyanate, isothiocyanate, dithiopyndine. vmylpyndine, lodoacetamide, epoxide, hydroxysuccmimidyl. azole, maleimide, sulfrne, allyl, vinylsulfone, tresyl, suifo-N-succmimidyl, dione, mesyl, tosyl, or glyoxal functionality with a biologically-ac ti ve compound or precursor thereof In some embodiments, Z is methyl and n is one P is a polyalkylene glycol polymer as defined above, and can be represented by Formula IT (Formula Removed) whcre E is hydrogen, a stiaight- or branched-chain d to C2o alkyl group (e g, methyl), a detectable label, or a moiety suitable for forming a bond between the compound of Formula XXII and J biologically-active compound or precursor thereol As above, a is an integer from 4 to 10,000 Where E is a detectable label, the label can be, for example, a radioactive isotope, a fluorescent moiety, a phosphorescent moiety, a chemilvnmnescent moiety, or a quantum dot. When E is capable of forming a bond to a biologically-active molecule or precursor thereof, a bifunctional molecule results E can form a bond to another molecule of the biologically-active compound (B) so that the activated polyalkylene glycol compound is bound at either tennmus to a molecule of the same type of biologically active compound, to produce a dimer of the molecule. In some embodiments, B forms a bond to a hologieally-active compound other than B, creating a hctcrodimer of biologically-active compounds or precursors thereof, In other embodiments, E forms an additional bond to the biclogically-active compound, B, such that both E and R are bound through different functional groups of the same molecule of the biologically-active compound or precuisor thereol. When E is capable of forming a bond to a biologically-active molecule or precursor thereof, E can he the same as 01 different from R and is chosen from carboxyhc acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, metbacrylate, acrylamidc, substituted or rmsubshtuted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazidc, succimmidyl, isocyanatc, isothiocyanate, dithiopyridme, vmylpyridme, lodoacetamide, epoxide, hydroxysuccuurmdyl, azole, malermide, sulfone, allyl, vinylsulfone, tresyl, sulfo-N-succmimidyl, dione, mesvl, tosyl, and glyoxal moieties In some embodiments, E can have the structure according to Formula 171 or Formula IV (Formula Removed) Z where each Q, X, Y, Z, m, and n are, independently, as defined above, each W is, mdependently, hydrogen or a C1 to C7 alky], R' is a moiety suitable for forming a bond between the compound of Formula III and a biologically-active compound or precursor thereof, and R'" is A moiety suitable for forming a bond between the compound of Formula IV and a biologicaliy-aclwe compound or precursor thereof R" and R'"' are, independently chosen trom carboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, nicthacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succmimidyl, isocyanate, lbothiocyanate, dithiopyndine, vmylpyndme, lodoacetamide, epoxide, hydroxy succmimidyl, azole, maleimidc, sulfone, ally!, vmylsulfone, tresyl, sulfo-N-succimmidyl. dione, mesyl, tosyl, and glyoxal moieties, and can be the same or different from R When bound at both ends to a biologically-actrve compound or precursor thereof, these bifunctional molecules can be represented according to Formula XXIV or Formula XXV: (Formula Removed) where each X and Y is independently O, S, CO, CO2, COS, SO, SO2, CONR', SC^NR5, or NR', and each R' and Z is, independently, hydrogen, a straight- or branched-chain, saturated or unsaturated C1 to C20 alkyl or hcteroalkyl group Q is a C1 to C8 saturated or unsaturated cyclic alkyl or cyclic heteroalkyl (including fused bicychc and bridged bicyclic ring structures), a substituted or unsubstituted aryl or heteroaryl group, or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group If present, the subshtuents can be halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, tluocarbonyl, thioester, thioacetnte, thioformate. alkoxyl, phobphory], phosphonate, phosplunate, amino, aruido, amidtne, imrne, cyano. nitro, azido, sulfliydry], sulfate, sulfonate, sulfamoyl, sulfonanndo, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, or alkylthio Each W is, independently, hydrogen or a C , to C7 alkyl. m is zero or one, a is an integer from A to 10,000. and each n is independently 0 or an integer from \ to 5 R* and R*+ are independently linking moieties as described above, B and B' are independently biologically-active molecules and can be the same or different. E (through R" 01 R'") can form a bond to another molecule of the biologically-active compound (B) so that the activated polyalkylene glycol compound is bound at either terminus to a molecule of the same type of biologically-active compound, to produce a dimer of the molecule In some embodiments, E (through R" or R'") forms a bond to a biologically-active compound otlier than B, creating a heterodimer of bio logically-active compounds or precursors thereof In other embodiments, E (through R" or R'") forms an additional bond to the biologically-active compound, B, such that both t and R are bound through different functional groups of the same molecule of the biologically-active compound or precursor thereof R" and R'" can be the same as or different from R, and are chosen from carboxytic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylarmde, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succinimidyl, isocyanate, isothiocyaiiate, dithiopyridfne, vmylpyndme. iodoacetamide. epoxide, hydroxysuccmimidyl, azole, maleimide, sulfone, ally], vinylsuifone, tresyl, sulfo-N-succinimidjl, dione, mesyl, tosyl, and glyoxal moieties In some embodiments, R* or R** is a methylene group and B or B' is a biologically-active molecule contaimng an amino group, where the methylene group fonus a bond with the amino group on B For example, the amine can be the ammo terminus of a peptide, an amine of an ammo acid side chain of a peptide, or an amine of a glycosylation substituent of a glycosylated peptide In some embodiments, the peptide is an interferon, such as mterferon- beta, e.g., interferon-beta-1 a. In some embodimeuts, this type of bond is formed by a reductive alkylution reaction The conjugates of the invention can be prepared by coupling a biologic ally-active compound to a polyalkylene glycol compound as described in the Examples. In some embodiments, the coupling is achieved via a reductive alky latum reaction Biologically-active compounds of interest include any substance intended for diagnosis, cure mitigation, treatment, or pievention of disease m humans or other animals, or to otherwise enhance physical or mental well-being of humans or animals. Examples of biologically-active molecules include, but are not limited to, peptides, peptide analogs, proteins, enzymes, small molecules, dyes, lipids, nucleosides, oligonucleotides, analogs of oligonucleotides, sugars, oligosaccharides, cells, viruses, liposomes, micrnpartitles, surfaces and micelles This class of compounds also include precursors of these types of molecules Gasses of biologically-active agents that are suitable for use with the invention include, but are not limited to, cytokines, chemofanes, rymphokmes, soluble receptors, antibodies, antibiotics, fungicides, anti-viral agents, anti-mflammatory agents, anti-tumor agents, cardiovascular agents, anti-anxiety agents, hormones, growth factors, steroidal agents, and the like The biologically-active compound can be a peptide, such as an interferon, including interferon-beta (e.g., mterferon-beta-la) or mterferon-alpha Because the polymeric modification with aPGC of the invention reduces antigenic responses, a foreign peptide need not be completely autologous in order to be used as a therapeutic For example, a peptide, such as interferon, used to prepare polymer conjugates may be prepared from a mammalian extract, such as human, raminant, or bovine interferon, or can be synthetically or recombinantly produced. For example, in one aspect, the invention is directed to compounds and methods for treating conditions that are susceptible of treatment with interferon alpha or beta Administration of a polyalkylene glycol conjugated mteiferon beta (hereinafter "PGC IFN-beta". "PGC IFN-(3", c g, PEG IEN-beta", "PEG IFN-fr "PEGylated JFN-beta", or "PEGylated IFN-(3") provides improved therapeutic benefits, while substantially reducing or eliminating entirely the undesirable side effects normally associated with conventionally practiced interferon alpha or beta treatment regimes The PGC IFN-beta can be prepared by attaching a polyalkylene polymer to the terminal amino group of the IFN beta molecule A single activated polyalkylene glycol molecule can be conjugated to the N-termmus of IFN beta via a reductive alkylation reaction. The PGC IFN beta conjugate can be formulated, for example, as a liquid or a lyophilized powder for injection. The objective of conjugation of IFN beta with a PGC is to improve the delivery of the protem by significantly prolonging its plasma half-life, and thereby provide protracted activity of IFN beta. The term "interferon" or "IFN" as used herein means the family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation and modulate immune response Human interferons are grouped into two classes; Type 1, including a- and p-rnterferon, and Type II, which is represented by y-interferon only. Recombinant forms of each group have been developed and are commercially available. Subtypes in each group are based on antigenic/structural characteristics The terms "beta interferon", "beta-interferon", "beta IFN", "beta-lFN", "p interferon", "p-interferon", "P IFN", "p-TJFN", "interferonbeta", "interferon-bcta", "interferon P", "mterferon-p", "IPN beta", "IFN-beta", "IFN0", "IFN-p", and "human fibroblast interferon" are used interchangeably herein to describe members of the group of interferon beta's which have distinct amino acid sequences as have been identified by isolating and sequencing DNA encoding the peptides Additionally, the terms "beta interferon la", "beti interferon-la" "beta-interferon la", "beta-mterferon-la", "beta IFN la", "beta IFN-la", "beta-TFN la", "beta-IFN-la". "p interferon la", "p interferon-la", "p-mterferon la", "p-interferon-la", "P IFN la", "piFN-la", "p-iFN la". "jMFN-la", "interferon beta la", "interferon beta-la", 'interferon-beta la", "interferon-beta-la", "interferon P la", 'interferon P-la", "interiemn-p la", "interferon-ß-la", "IFNbcta la", "IFN beta-la", "IFN-beta la", "IFN-beta-la". "IFN P la", "IFN p-la", "IFN-p la", "IFN-P-la" are used interchangeably herein to describe recombinantly- or synthetically-produced interferon beta that has the naturally-occuriing (wild type) amino acid sequences The advent of recombinant DNA technology applied to interferon production has permitted several human interferons to be successfully synthesized, thereby enabling the large-scale fermentation, production, isolation, and purification of various interferons to homogeneity. Recombinantly produced interferon retains some- or most of- its in \itro and in vivo antiviral and immunomodulatory activities It is also understood that recombinant techniques could also include a glycosylation site for addition of a carbohydrate moiety on the recombinantly-denved polypeptide. The construction of recombinant DNA plasmids containing sequences encoding at least part of human fibroblast interferon and the expression of a polypeptide having immunological or biological activity of human fibroblast interferon is also contemplated. The construction of hybrid beta-vnterferon genes containing combinations of different subtype sequences can be accomplished by techniques known to those of sbll in the art Typical suitable recombinant beta-interfcrons which may be used in the practice of the invention include but are not limited to interferon beta-la such as AVONEX* available from Biogen, Inc., Cambridge, MA, and mlerferon-beta-lb such as BETASERON* available from Berlex, Richmond, CA. There are many mechanisms by which IFN-induced gene products provide protective elfects against viral infection Such inhibitory viral effects occur at different stages of the viral life cycle See U.S Patent No 6,030,785 For example, IFN can inhibit uncoatmg of viral particles, penetration, and/or fusion caused by viruses Conditions that can be treated in accordance with the present invention are generally those that are susceptible to treatment with interferon For example, susceptible conditions include those, which would lespond positively or favorably (as these terms arc lenown in the medical arts) to interferon beta-based therapy For purposes of the invention, conditions that can be treated with interferon beta therapy described herein include those conditions in which treatment with an interferon beta shows some efricacy, but in which tire negative side effects of BFN-p treatment outweigh the benefits Treatment according to the methods of the invention results in substantially reduced or eliminated side effects ds compared to conventional interferon beta treatment. In addition, conditions traditionally thought to be refractory to JFN-P treatment, or those for which it is impractical to treat with a manageable dosage of IFN-p, can be treated in accordance with the methods of the present invention. The PGC IFN-P compounds of the invention can be used alone or in combination with one or more agents useful for treatment for a particular condition. At least one pilot study of recombinant interferon beta-la for the treatment of chronic hepatitis C has been conducted See generally Habeisetzer et al, Liver 30:437-441 (2000), incorporated herein by reference. For example, the compounds can be administered in combination with known antiviral agents for treatment of a viral infection. See Kakumu et al, Gastroenterology 105 507-12 (1993) and Pepinsky, et al, J. Pharmacology and Experimental Therapeutics, 297.1059-1066 (2001), incorporated herein by reference As used herein, the term "antivirals" may include, for example, small molecules, peptides, sugars, proteins, virus-derived molecules, protease inhibitors, nucleotide analogs and/or nucleoside analogs, A 'small molecule" as the term is used herein refers to an organic molecule of less than about 2500 amu (atomic mass units), preferably less than about 1000 amu Examples of suitable antiviral compounds include, but are not limited to, ribavirin. levovkin, MB6S60, zidovudine 3TC, FTC, acyclovir, gancyclovir, viramide, VX-497, VX-950, and IS1S-14803. Exemplary conditions which can be treated with interferon include, but are not limited to, cell proliferation disorders, in particular multiple sclerosis, cancer (e.g., hairy cell leukemia, Kaposi's sarcoma, chronic myelogenous leukemia, multiple myeloma, basal cell carcinoma and malignant melanoma, ovarian cancer, cutaneous T cell lymphoma), and viral infections. Without limitation, tieatment with interferon may be used to treat conditions which would benefit from inhibiting the replication of rnterferon-sensitive viruses. For example, interferon can be used alone or m combination with AZT in the treatment of human immunodeficiency virus (HIV)/AIDS or m comhmdtion with ribavirin m the treatment of HCV. Viral infections which may be treated in accordance with the invention include, but are not limited to, hepatitis A, hepatitis B, hepatitis C, other non-A/non-B hepatitis, herpes virut., Epstein-Barr virus (LBV), cytomegalovirus (CMV), herpes simplex, human herpes virus type 6 (HIIV-6), papilloma, poxvirus, picornavmis, adenovirus, rhmovrrus, human T lymphotropic virus-type 1 and 2 (HTLV-1/-2), human rotavirus, rabies, retroviruses including HIV, encephalitis, and respiratory wal infections The methods of the invention can also be used to modify various immune responses. A correlation between HCV genotype and response to interferon therapy has been observed See U.S Patent No 6,030,785, Enomoto et al, N. Engl. J. Med.334:77-Sl (1996); Enomoto et al, J Clin. Invest 96.224-30(1995). The response rate in patients infected with HCV-lbis less than 40% See U.S. Patent No 6,030,785 SirmlaT low response rates have also been observed in patients infected with HCV-1 a. See id, Hoofhagel et al.. Intervirology 37:87-100 (1994). However, the response rate in patients infected with HCV-2 is nearly 80% See U.S Patent No 6,030,785, Fried et a]., Semm. Liver Dis. 15-82-91 (1995). In fact, an amino acid sequence oi a discrete region of the NS5A protein of HCV genotype lb was found to correlate with sensitivity to interferon. See US Patent No 6,030,785, incorporated herein by reference See also Enomoto et al 1996, Enomoto et al. 1995 Tins region has been identified as the interferon sensitivity determining region (ISDR). See id. f he PGC EFN-beta conjugate is administered in a pharmacologically-efiectivc amount to treat any of the conditions described above, and is based on the IFN beta activity of the polymeric conjugate The term "pharmacologically-effective amount" means the amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal oi human that is being sought by a researcher or clinician It is an amount that is sufficient to significantly affect a positive clinical response while maintaining diminished levels of side effects. The amount of PGC IFN-beta which may be administered to a subject in need thereof is in the range of 0.01-100 µg/kg, or more preferably 0.01-10 µg/kg, administered m single or divided doses Administration of the described dosages may be every other day, but preferably occurs once a week or once every other week. Doses are administered over at least a 24 week period by injection. Administration of the dose can be oral, topical, intravenous, subcutaneous, intramuscular, or any other acceptable systemic method. Based on the judgment of the attending clinician, the amount of drug administered and the treatment regimen used will, of course, be dependent on the age, sex and medical history of the patient being treated, the neutrophil count ( g., the seventy of the neutropenia), the severity of the specific disease condition and the tolerance of the patient to the treatment as evidenced by local toxicity and by systemic side-effects In practice, the conjugates of the invention are administered in amounts which will be sufficient to inhibit or prevent undesired medical conditions or disease in a subject, such as a mammal, and are used in the form most suitable for such purposes. The compositions are preferably suitable for internal use and include an effective amount of a pharmacologically-active compound of the invention, alone or in combination with other active agents, with one or more pharmaceutically-acceptable carriers. The compounds are especially useful in that they have very low, if any, toxicity. The conjugates herein described can form the active ingredient of a pharmaceutical composition, and are typically administered in a mixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like. The compositions typically will include an effective amount of active compound or the pharmaccuticaily-acceptable salt thereof, and in addition, and may also include any earner materials as are customarily used in the pharmaceutical sciences Depending on the intended mode of administration, the compositions may be in solid, semi-solid or liquid dosage form, such as, for example, injcctables, tablets, suppositories, pills, time-release capsules, powders, liquids, suspension4;, or the like, preferably in unit dosages. Conventional pharmaceutical compositions comprising a pharmacologically-effective amount of a conjugate, e g, PGC IFN-bera, together with pharmaceutically-acceptabk earners, adjuvants diluents, preservatives and/or solubilizets may be used in the practice of the invention. Pharmaceutical compositions of interferon include diluents of various buffers (e.g, arginine, Tns-HCl, acetate, phosphate) having a range of pH and ionic strength, carriers (e g, human serum albumin), solubilizcrs (eg., twcen, polysorbate), and preservatives (e g, benzyl alcohol). See, for example, U.S. Pat. No 4,496,537 Administration of the active compounds described herein can be via any of the accepted modes of administration for therapeutic agents. These methods include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, or topical administration modes For instance, for oral administration in the form of a tablet or capsule (e.g., a gelatin capsule), the active drug component can be combined with an oral, non-toxic pharmaceutically-acceptable inert earner such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carhoxymethyluellulose and/or polyvinylpyrrolidone, sugars, com sweeteners, natural and synthetic gums such as acacia, tragacanth OT sodium alginate, polyethylene glycol, waxes and the like. Lubricants used m these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chlonde, silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethylene glycol and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum starches, agar, algvnic acid or its sodium salt, or effervescent mixtures, and the like. Diluents, include, e.g., lactose, dextrose, sucrose, manrutol, sorbitol, cellulose and/or glycine. The conjugates of the invention can also be administered in such oral dosage forms as timed-release and sustained-release tablets or capsules, pills, powders, granules, elixcrs, tinctures, suspensions, syrups, and emulsions. Liquid, particularly injectable compositions can, for example, be prepaied by dissolving, dispersing, etc The active compound is dissolved m or mixed with a pharmaceutically-pure solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol. and the like, to thereby form the injectable solution or suspension. Additionally, solid forms suitable for dissolving in liquid prior to injection can be formulated. Injectable compositions are preferably aqueous isotonic solutions or suspensions. The compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically-valuable substances. The conjugates of the present invention can be administered in intravenous (e.g., bolus or infusion), intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. Injectables can be prepared m conventional forms, either as liquid solutions or suspensions Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions For example, when a subcutaneous injection is used to deliver 0 01-100 (ig/kg, or more preferably 0 01-10 pg/kg of PEGylated IfN-beta over one week, two injections of 0 005-50 u.g/kg, or more preferably 0.005-5 ug/kg, respectively, may be administered at 0 and 72 hours. Additionally, one approach for parenteral administration employs the implantation of a slow-release or sustained-released system, which assures that a constant level of dosage is maintained, according to U S. Pat No 3,710.795, incorporated herein by reference. Furthermore, preferred conjugates for the present invention can be administered m intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of Lransderma] skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than mtermittent throughout the dosage regimen. Other preferred topical preparations include creams, ointments, lotions, aerosols, sprays and gels, wherein the amount administered would be 10-100 times the dose typically given by parenteial administration. For solid compositions, excipients include pharmaceutical grades of mannitol, lactose, starch, magnesium stcarate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like may be used. The active compound defined above, maybe also formulated as suppositories using for example, polyalkylene glycols, for example, propylene glycol, as the carnei. In some embodiments, suppositories are advantageously prepared from fatty emulsions or suspensions. The conjugates of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine, or phosphatidylcholines In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat No 5,262,564 Conjugates of the present invention may also be delivered by the use of immunoglobulin fusions as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug earners. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl-methacrylamide-phenol, polyhydroxyethylaspanarnidephenol, or polyethyleneoxidepolylysme substituted with palmitoyl lesidues. The conjugates can also be coupled to proteins, such as, for example, receptor proteins and albumin. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthocsters, poly acetate, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels if desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxihary substances such as wetting or emulsifying agents, pH buffering agents, and other substances such as for example, sodium acetate, triethanolamine oleate, etc. The dosage regimen utilizing the conjugates is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity oi the condition to be treated, the route of admmistration, the renal and hepatic function of the patient; and the particular compound or salt thereof employed. The activity of the compounds of the invention and sensitivity of the patient to side effects are also considered. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01-100 u.g/kg/day orally, or more preferably 0.01-10 ug/kg/day orally. The compositions are preferably provided in the form of scored tablets containing 0.5-5000 ug, or more preferably 0.5-500 iig of active ingredient. For any route of administration, divided or single doses may be used For example, compounds of the present invention may be administered daily or weekly, in a single dose, or the total dosage may be administered in divided doses of two, three or four. Any of the above pharmaceutical compositions may contain 0.1-99%, 1-70%, or, preferably, 1 -50% of the active compounds of the invention as active ingredients As described above, the course of the disease and its response to drug treatments may be followed by clinical examination and laboratory findings. The effectiveness of the therapy of the invention is determined by the extent to which the previously described signs and symptoms of a condition, e g. chronic hepatitis, are alleviated and the extent to which the normal side effects of interferon (i e., flu-like symptoms such as fever, headache, chills, myalgia, fatigue, etc and central nervous system related symptoms such as depression, paresthesia, impaired concentration, etc.) are eliminated or substantially reduced. In home embodiments, a polyalkylated compound of the indention (e.g.. a PKGylated interferon) is administered in conjunction with one or mure pharmaceutical agents useful for treatment lor a particular condition. For example, a polyalkylated protein can be administered in combination with a known antiviral agent or agent for treatment of a viral infection. Such antiviral compounds include, for example, nbavirin, levovtnn, MB 6866, and zidovudine 3TC, FTC, acyclovir, gancyclovir. vimmide, VX-497, VX-950, and ISIS-14803. The conjugate and antiviral can be simultaneously administered {e.g„ the agents are administered to a patient together); sequentially administered (e g., the agents are administered to the patient one after the other); or alternatively administered (e g., the agents are administered in a repeating series, such as agent A then agent B, then agent A, etc.). In the practice of the invention, the preferred PGC IFN-bcta (eg, PEG IFN-bcta) may be administered to patients infected with the hepatitis C virus. Use of PEG EFN-beta-la is preferred Patients are selected for treatment from anti-HCV antibody-positive patients with biopsy-documented chronic active hepatitis. In order to follow the course of HCV replication in subjects in response to drug treatment, HCV RNA may be measured in serum samples by, for example, a nested polymerase chain reaction assay that uses two sets of pnmers derived from the NS3 and NS4 non-structural gene regions of the IICV genome See Farci et al., 1991, New Eng. J Med 325:98-104 Utrich et al, 1990. J Clin Invest, 861609-1614. Antiviral activity may be measured by changes m HCV-RNA titer. HCV RNA ddta may be analyzed by comparing titers at the end of treatment with a pre-treatrnent baseline measurement. Reduction in HCV RNA by week 4 provides evidence of antiviral activity of a compound. See Kkter et al-, 1993, Antimicrob. Agents Chemother. 37(3):595-97; Onto et al., 1995, J. Medical Virology, 46 109-115. Changes of at least two orders of magnitude (>2 log) is interpreted as evidence of antiviral activity. A person suffering from chrome hepatitis C infection may exhibit one or more of the following signs or symptoms (a) elevated serum alanine aminotransferase (ALT), (b) positive test tor anti-HCV antibodies, (c) presence of HCV as demonstrated by a positive test for HCV-RNA, (d) cluneal stigmata of chronic liver disease, (e) hepatocellular damage. Such criteria may not only be used to diagnose hepatitis C, but can be used to evaluate a patient's response to drug treatment Elevated alanine; ammohansferase (ALT) and aspartate aminotransferase (AST) are known to occur m uncontrolled hepatitis C, and a complete response to treatment is generally defined as the nonnalization of these serum enzymes, particularly ALT See. Davis et al., 1989, New Eng. J. Med. 321:1501-1506. ALT is an enzyme released when liver cells are destroyed and is symptomatic of HCV infection Interferon causes synthesis of the enzyme 2',5'-oligoadenylate synthetase (2'5'OAS), which in turn, results in the degradation of the viral mRNA. See Houglum, 1983, Clinical Pharmacology 2 20-28 Increases in serum levels of the 2'5'OAS coincide with decrease in ALT levels. Histological examination of liver biopsy samples may be used as a second criteria for evaluation. See. e,g,, Knodell et al„ 1981,Hepatology 1-431-435, whose Histological Activity Index (portal inflammation, piecemeal or bridging necrosis, lobular injury, and fibrosis) provides a scoring method for disease activity. Safety and tolerabihty or treatment may be determined by clinical evaluations and measure ot white blood cell and neutrophil counts This may be assessed through periodic monitoring of hematological parameters e g, white blood cell, neutrophil, platelet, and red blood cell counts). Various other extended- or sustained-release formulations can be prepared using conventional methods well known in the art. Many modifications and variations of this invention can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. The specific embodiments described herein are offered by way of example only, and the invention is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled All patents and publications cited herein are incorporated by reference EXAMPLES EXAMPLE 1: Synthesis of activated polyalkylene glycols A) Alkylation of alcohols Activated polyalkylene glycols are synthesized by alkylating a polyalkylene glycol having a free terminal hydroxyl functionality. A generic reaction is outlmed in Scheme I: Scheme I (Scheme Removed) The polyalkylene glycol (P-OH) is reacted with the alkyl halide (A) to form the ether (B) Compound B is then hydroxylated to form (he alcohol (C), which is oxidized to the aldehyde (D). In these compounds, n is an integer from zero to five and Z can be a straight- or branched-cham, saturated or unsaturated C1 to C20 alkyl or hctcroalkyl group Z can also be a C3 to C7 saturated or unsatuiated cyclic alkyl or cyclic hctcroalkyl. a substituted or umubstituted aryl or heteroaryl group, or a substituted or unbubshtuted alkaryl (the alky! is a C1 to C20 saturated or unsaturated alkyl) or heleroalkaryl group. For substituted compounds, the substituents can be halogen, hydroxyl. carbonyl, carboxylate, ester, formyl, acyl, thiocaibonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, pbosphrnate. amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonarnido, sulfonyl, heterocyclyl, aralkyl, aiomahc moiety, heteroaromatic moiety, immo, silyl, ether, or alkylthio. Typically, POH is polyethylene glycol (PEG) or monomethoxy polyethylene glycol (mPBG) having a molecular weight of 5,000 to 40,000 Daltons (Da) For example, the synthesis of mPEG-O-2-metbylpropionaldehyde is outlined in Scheme II Scheme II (Scheme Removed) mPEG-OH with a molecular weight of 20, 000 Da (mPEG-OH 20 kDa; 2.0 g, 0.1 nimol, Sunbio) was treated with NaH (12 mg, 0 5 mmol; in THF (35 mL). Fifty equivalents of 3-bromo-2-methylpropene (3.34 g, 5 mmol) and a catalytic amount of KI were then added to the mixture The resulting mixture was heated to reflux for 16 h Water (1 mT,) was then added and the solvent was removed under vacuum To the residue was added CHjCh {25 iwL) and the organic layer was separated, dried over anhydrous Na2SO.i, and the volume was reduced to approximately 2 mL. This CH2CL solution was added to ether (150 mL) drop-wise The resulting white precipitate was collected, yielding 1.9 g of compound l_ 1HNMR (CDCLJ, 400 MHz) showed S 4 98 (s, 1H), 4.91 (s, 1H), 1 74 (s, 3H) To compound 1(3 9 g, 0.1 mmol) in THF (20 mL) and CH2C12 (2 mL) at 0°C, was added BH3 in THF (1 0 M, 3.5 mL). The mixture was stirred in an ice bath for 1 h. To this mixture, NaOH was added slowly (2.0 M, 2.5 mL), followed by 30% H202 (0.8 mL). The reaction was warmed to room temperature and stirred for 16 h The above work-up procedure was followed (CH2G2, precipitated from ether) to yield 1 8 g of 2 as a white solid. 1HNMR (CDCLJ, 400 MHz) showed 5 1.80 (m, 1H), 0 84 (d, 3H). Compound 2 (250 mg) was dissolved m CH2C12 (2.5 mL) and Dess-Martin pcriodinate (DMP; 15 mg) was added with stirring for 30 mm at room temperature. To the mixture was added saturated NaHCO) and NajSiOj (2 mL) and the mixture was stirred at room temperature for 1 h. The above work-up procedure was followed to give 3 (mPEG-O-2-methylpropionaldehyde, 120 mg) as a white solid 1HNMR (CDC13, 400 MHz) showed 5 9 75 (s, ill), 2 69 (m, 1H), 1 16 (d. 3H) A similar procedure is followed for aromatic alcohols, as shown in Scheme LTI. Scheme III (Scheme Removed) In general, the aromatic alcohoi (E) is reacted with the alky] balide (A) to form the mono ether (F). The remaining alcohol group of compound F is then converted to the halide (e.g., bromide) in Compound G, which is reacted with the polyaUcylene glycol (P-OH) to give the ether (H) This compound is then converted to the aldehyde (J) througli a hydroboration to the primary alcohol (I) followed by oxidation. In these compounds, n is an integer from zero to five, d is zero or an integer from one to four, and Z uan be a straight- or branthed-chain, saturated or unsaturated C1 to Cw alky] or heteroalkyl group. Z can also be a C3 to C7 saturated or unsaturated cyclic alky! or cyclic heteroalkyl, a substituted or unsubshtutcd aryl or heteroaryl group or a substituted or unsubstituted alkaryl (the alkyl is a C1 to Cyi saturated or unsaturated alkyl) 01 heteroalkaryl group. For substituted compounds, the subslituents can be halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, tlu'oformatc, alkoxyl, phosphoryl, phosphonate, phosphinate, ammo, amido, amidine, inline, cyano, mtro, azido, sulfliydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, suJfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, or alkyhhio. Additionally, Ti and T2 are, independently, absent, or a straight- or branched-chain, saturated or unsaturated C| to C20 alk>'l or hcteroalkyl group, and can be ortho, mcta, or para to each other. Each L (when present) is, independently, a straight- or branched-chain, saturated or unsaturated C1 to C20 alkyl or heteroalkyl group. C3 to C7 saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to Ci0 saturated or unsaturated alkyl or heteroalkaryl group. The substitucnts can be halogen, hydroxy], carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate. thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido. amidine, imme, cyano, nitro, azido, sulfliydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, or alkyltluo Usually, P-OH is polyethylene glycol (PEG) or monomethoxy polyethylene glycol (mPEG) having a molecular weight of 5,000 to 40,000 Da For example, the synthesis of mPEG-O-ß-mcthylphenyl-O-2-methylpropionaldehyde (8) is shown m Scheme IV; Scheme IV (Scheme Removed) To a solution of 4-hydroxybenzylalcohol (2 4 g, 20 mmol) in THF (50 mL) and water (2.5 mL) was first added sodium hydroxide (1 5 g, 37 5 mmol) and then 3-brnmn-2-methylpropcne (4 1 g, 30 mmol). This reaction mixture was healed to reflux for 16 h. To the mixture was added 10% utnc acid (2.5 mL) and the solvent was removed under vacuum. The residue was extracted with ethyl acetate (3x15 mL) and the combined organic layers were washed with saturatedNaCl (10 mL), dried and concentrated to give compound+, (3.3 g, 93 %) 1HNMR (CDC13, 400 MHz) showed δ 7 29 (m, 2IT). 6 92 (m, 2H), 5 14 (s, 1H), 5 01 (s, 1H), 4.56 (s, 2H), 4.46 (s, 211), 1.85 (s, 3H) Mesyl chloride (MsCl, 2.5 g, 15.7 mmol) and triethyl amine (TEA; 2.8 mL, 20 mmol) were added to a solution of compound 4 (2,0 g, 11 2 mmol) in CH1Cl2 (25 mL) at 0°C and the reaction was placed in the refrigerator for 16 h A usual work-up yielded a pale yellow oil (2 5 g, 87%). 1HNMR(CDC13, 400 MHz) showed 5 7.31 (m, 2H), 6.94 (m, 2H), 5 16 (s, 1H), 5.01 (s. 1H), 5 03 (s, 2H), 4 59 (s, 2H), 4.44 (s, 2H), 3.67 (s, 3H), 1.85 (s, 3H) This oil (2 4 g, 9.4 mmol) was dissolved m THF (20 mL) and LiBr (2 0 g, 23 0 mmol) was added The reaction mixture was heated to reflux for 1 h and was then cooled to room temperature. Water (2 5 mL) was added to the mixture and the solvent was removed under vacuum The residue was extracted with ethyl acetate (3 x 15 mL) and the combined organic layers were washed with saturated MaCl (10 mL), dried over anhydrous Na2SO4, and concentrated to give the desired bromide 5 (2 3 g, 96%) as a pale yellow oil, 1H NMR (CDCl3, 400 MHz) showed 5 7 29 (m, 2H). 6 88 (m, 2H). 5 11 (s, III), 4 98 (s, 1H), 4.53 (s. 2H), 4 44 (s, 2H), 1 83 (s, 3H) mPEG-OH 20 kDa (2 0 g, 0 1 mmol, Sunbio) was treated with NaH (12 mg, 0.5 mmol) m TKF (35 mL) and compound 5 (0 55 g, 22.8 mmol) was added to the mixture with a catalytic amount of KI The resulting mixture was heated to reflux for 16 h Water (1 0 mL) was added to the mixture and the solvent was removed under vacuum To the residue was added CH2Cl2 (25 mL) and the organic layer was separated, dried over anhydrous Na2SO4, and the volume was reduced to approximately 2 mL, Drop-wise addition to an ether solution (150 mL) resulted in a white precipitate which was collected to yield 6 (1.5 g) as a white powder 1HNMR (CDC13- 400 MHz) showed 8 7.21 (d. 2H), 6 90 (d. 2H), 5 01 (s, 1H), 4.99 (s, 1H). 4 54 (s, 2H), 4.43 (s, 2H), 1 84 (s, 3H). To a solution of compound 6(1.0 g, O.05 mmol) m IHF (10 mL) and CH2Cl2 (2 mL) cooled to 0°C, was added BH3/THF (1.0 M. 3.5 mL) and the reaction was stirred for 1 h. A 2 0 M NaOH solution (2.5 mL) was added slowly and followed by 30% H202 (0.8 mL) The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The above work-up procedure was followed (CH2Cl2. precipitated from ether) to yield 7 (350 mg) as a white solid 1HNMK (CDC13.400 MHz) showed 8 7,21 (d, 2H), 6.84 Similarly, mPEG-O-m-methylphenyl-O-2-methylpropionaldehyde (9) was synthesized as outlined in Scheme V Scheme V. (Scheme Removed) To a solution of 3-hydruxybenzyljlcohol (2 4 g, 20 mmol) in THF (50 mL) and water (2 5 mL) was first ddded sodium liydi oxide (1 5 g, 31 5 mmol) and then 3-bromo 2-methylpropcnc (4 1 g, 30 mmol) This reaction mixture was heated to refhix for 16 h To the mivluTe was added 10% citric acid (2 5 mLl and the solvent was removed under vacuum Tire re MsCl (2 5 g, 15 7 mmol) and TEA (2 8 mL, 20 mmol) were added to a solution of compound 1JJ (2 0 g, 11 2 mniol) 111 CH2Cl2(25 mL) at 0"C and the reachon was placed in the refrigerator for 16 h A usual work-up yielded a pale yellow oil (2 5 g, 87%). 1HNMU (CDCb, 400 MHz) showed 5 7 31 (m, 1H), 7 05 (m, 2H), 6 91 (m, 1H), 5 16 (s, 1H), 5 04 (s, 1H), 4 59 (s, 1H), 4.46 (s, 2IT), 3 71 (s, 3H), 1 84 (s, 3H) This oil (2 4 g, 9 4 mmol) was dissolved in THF (20 mL) and LiBr (2 0 g, 23 0 mmol) was added The reaction mixture was heated to reflux for 1 h and was then coded to room temperature To the mixture was added water (2 5 mL) and Hie solvent was removed under vacuum The residue was extracted with ethyl acetate (3*15 mL) and the combined organic layers were washed with saturated NaCl (10 mL), dried over nnhydrous Na;iSO4, and concentrated to give the desired bromide 11 (2 2 g, 92 %) as a rale yellow oil ' HNMR (CDCb, 400 MHz) showed S 7 29 (m, 1H), 6 98 (m, 2H), 6-85 (m, 1H), 5 14 (s, 2H). 4 9S (s, 2H), 4 50 (s. 2H), 4 4-J (s, 2H), 1 82 (d, 3H) mPEG-OH 20 kDa (2 0 g, 0.1 mmol, Sunbio) was treated with NaH (12 mg, 0 5 mmol) in THF (35 mL) and compound JJ, (0.55 g, 22 8 mmol) was added to the mixture with a catalytic amount of Kl The resulting mixture was heated to reflux for 16 h. Water (1.0 mL) was added to the mixture and the solvent was removed under vacuum. To the residue was added CH2CL (25 mL) and the organic layer was separated, dried over anhydrous Na2SO4, and the volume was reduced to approximately 2 mL Drop-wise addition to an ether solution (150 mL) resulted in a white precipitate which was collected to yield 12 (1.8 g) as a white powder 1HNMR (CDC1,, 400 MHz) showed 6 7.19 (m, 1H), 6.88 (m, 2H), 6.75 (m, 1H), 4.44 (s, 2H), 4.10 (m,2H). 1.82 (d,3H), To a solution of compound 12 (1.0 g, 0.05 mmol) in THF (7.5 mL) and CH2C12 (2 5 mL) cooled to 0°C, was added BH3/THF (1 0 M, 3.5 mL) and the reaction was stirred for 1 h A 2 0 M NaOH solution (3 mL) was added slowly, followed by 30% II:02 (0.85 mL). The reaction mature was allowed to warm to room temperature and stirred for 16 h. The above work-up procedure was followed (CH2O2, precipitated from ether) to yield L3 (450 mg) as a white solid. 1HNMR (CDC13, 400 MIIz) showed 5 7.15 (m, 1H), 6 84 (m, 2H), 6.69 (m, 1H), 4 50 (s, 2H), 2 90 (m, 2 H), 1 95 (d, 3H). Compound 13 (200 mg, 0 01 mmol) was dissolved in CH2C12 (1 5 mL) and DMP (20 mg) was added while the reaction mixture was stirred at room temperature for 1 h HNMR (CDCk 400 MHz) showed 5 9.74 (s, 1H), 7.17 (m, 1H), 6 86 (m, 2H); 6.74 (m, 1H),4.48 (s. 2H), 4 15 (m, 2H), 2.78(m. 1H), 1.22 (d, 3H) To the mixture was added saturated NaHCO3 (0 5 mL) and Na2S2O3 (0.5 mL) and stirring (.ontinued at room temperature for I h. The above work-up procedure was followed (CH2Cl2 solution, precipitated from ether) to give 9 (142 mg) as a white solid B) Generation via Reaction with Aromatic Alcohols Activated polyalkylene glycols are .synthesized by a Mitsunobu reaction between a polyalkylene glycol having a free terminal hydroxyl functionality and an aromatic alcohol. The reaction scheme is outlined in Scheme VI (Scheme Removed) The polyalkylene glycol (P-OH) is reacted with an alcohol (K) to fomi the ether (L) In these compounds, m is zero or one, d is zero or an integer from one to four, and n is zeru or an integer from one to five V is O, S, CO, CO-,, COS, SO, SO2, CONR\ SO2NR\ and NR\ Ti and T2 are, independently, absent, or a straight- or branched-chain, saturated or unsaturated C1 to C20 alkyl or heteroalkyl group. R" and Z are, independently, hydrogen, a straight- or branched-chain, saturated or unsaturated C1 to Ojo alkyl or heteroalkyl group. Each L (if present) is, independently, a straight- or branched-chain, saturated or unsaturated C] to C21) alkyl or heteroalkyl group, C1 to C7 saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaiyl. The alkyl is a Q to C20 saturated or unsaturated alkyl or heteroalkaryl group, and the substituents can be halogen, hydroxy], carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thiocster, thioacctatc, thiofoimate, alkoxyl, phosphoryl, phosphorate, phosphmate, amino, amido, amidine, imine, cyano, nitro. azido. sulfhydryl, sulfate, sulfonate, sulfanaoyl, sulfonamide,, sulfonyl, heterocyclyl, aralky], aromatic moiety, heteroaromdlic moiety, unino, silyl, ether, or alkylthio. P is a polyalkylene glycol polymer. Usually. P-OH is polyethylene glycol (PEG) or monomethoxy polyethylene glycol (mPEG) havmg a molecular weight of 5, 000 to 40, 000 Da For example, a synthesis of mPEG-O-^-phenylacetaldehyde (16) is outlined in Scheme VIL Scheme VII (Scheme Removed) 4-hydroxyphenylacetaldehyde (15) was. synthesized as described in Heterocycles, 2000, 53, 777-784 4-Hydroxypbenethyl alcohol (Compound 14, 1.0 g, 7.3 mmol, Aldrich) was dissolved in dim ethylsulfoxide (8 mL, Aldrich). With stirring, TEA (2.2 mL, 16 mmol, Aldrich) was added slowly Pyndme-sulfiir trioxidc (SOj.py) complex (2 5 g, 16 mmol, AJdiich) was completely dissolved in dimetliylsulfoxidc (9 mL, Aldnch) and this solution was added drop-wise to the alcohol, with vigorous stirring After stirring for 1 b at room temperature, the reaction was diluted with CH2Cl2, then washed with ice-cold water The organic layer was dried over Na:SO4, filtered, and concentrated to dryness Purification using silica gel chromatography with liexane-ethyl acetate as cluent (51, then 2 1) yielded 488 mg (49%) of 4-hydroxyphenylacetaldehyde (15), mPEG-OII 20 kDa (101 mg, 0.005 mmol) and 4-hydroxyphenylacetaldehyde (15) (39 mg, 0.29 mmol) were azeotroped four times with toluene, then taken up in anhydrous CH2CI; (2 mL, Aldnch) To this solution was added triphenylphosphine (PPha, 66 mg. 0.25 mmol Aldrich) and then diisopropylazodicarboxylate (DIAD, 49 pL, 0 25 mmol, Mdrich) with strrrmg. After 3 days of stimng at room temperature, the reaction mixture was added drop-wise to vigorously-stirred diethyl ether The resulting precipitate was isolated by filtration and washed three times with diethyl ether. The crude material was taken up in CH2Cl2 and washed with water. The organic layer was dried over Na^O-i, filtered, and concentrated to dryness The material was taken up m minimum CH2Cb, then precipitated by adding drop-wise to stirred diethyl ether This material was collected by filtration, washed three times with diethyl ether and dried to give 63 mg (62%) of mPEG-O-/>-phenylacctaldehyde (161 A .synthesis of mPEG-O-ß-phenylpropionaldehyde (17) was prepared m a similar manner (Formula Removed) 4-hydroxyphenylpropionaldehyde was prepared by a synthesis analogous to that for 4-hydroxyphenylacetaldehyde (Heteracyctes, 2000,53. 777-784) 3-(4-Hydroxyphenyl)-l-propanol (1 0 g, 6 b mmol, Aldnch) was dissolved m dmielhylsulfoxide (8 mL. Aldnch) TEA (2 0 mL, 14 minol, Aldnch) was added slowly with stirnng Pyndine-sulfur tnoxidc (SQ>py) complex (2 3 g, 15 minol, Aldrich) was completely dissolved in dimethylsulfoxidc (9 mL, Aldrich) and tins solution was added drop-wise to the alcohol, with vigorous stirnng After slimng for 1 h at room temperature, the reaction was diluted with CH2Cl2, then washed with ice-cold water The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. Purification using silica gel chromatography with hexane-ethyl acetate as eluent (5.1, then 21) yielded 745 mg f/75%) of 4-hydro\yphenylpropionaldehyde mPEG-OH 20 kDa (100 nig, 0.005 mmol) and 4-hydrox>phenylpropionaldehydc (40 mg. 0.27 mmol) were azeotroped four Limes with toluene, then taken up m anhydrous Ct^Clj (2 mL, Aldnch) To this solution was added tnphenylphosphine (66 mg, 0 25 mmol, Aldrich) and then diisopropylazodicarboxylate (49 fiL, 0.25 mmol, Aldnch) with stirnng. After 3 days stirnng at room temperature, the reaction mixture was added drop-wise to vigorously-stirred diethyl ether lTie resulting precipitate was isolated by filtration and washed three times with diethyl elher The crude material was taken up m CH2Cl2 and washed with water The organic layer was dned overNa2SO4, filtered, and concentrated to dryness The material was taken up in minimum CH2O2, then precipitated by adding drop-wise to stirred diethyl ether This matenal was collected by iiltration, washed three times with diethyl ether and dned to give 60 mg (60%) of mPEG-O-^-phenylpropionaldehyde (17) mPEG-O-m-phenylacetaldehyde (18) was also prepared in tins way. (Formula Removed) 3-hydro.vyphenylacetaldehyde was prepared by a synthesis analogous to that of 4-hydroxyphenylacetaldchyde {Heterocvcles, 2000, 53, 777-784) 3-Hydroxyphenethyl "alcohol (1.0 g, 7 5 mmol, Aldnch) was dissolved in dimethylsulfoxide (8 mL, Aldnch) TEA (2 0 mL, 14 mmol, Aldnch) was added slowly with stirring Pyndine-sulfur tnoxide (SOj.py) complex (2.4 g, 15 mmol, Aldrich) was completely dissolved in dimethylsulfoxide (8 mL, Aldnch) and this solution was added drop-wise to the alcohol, with vigorous stirring After stirring for 1 h at room temperature, the reaction was quenched with ice-cold water, then extracted with CH^Ck The organic layer was dned over Na2SOj, filtered, and concentrated to dryness Purification using silica gel chromatography with hexane-ediyl acetate as eluent (3:1, then 1,1) yielded 225 mg (22%) of 3-hydxoxyphenylacetaldchyde mrEG-OH 20 kf)a (307 mg. 0 015 mmol) and 3-hydroxyphenylaeeLaldehyde (117 mg, 0 86 mmol) were azeotroped four times with toluene, then taken up ui anhydrous CUzCh (5 mL, Aldnch) To this solution was added triphenylphosphine (200 mg, 0.76 mmol, Aldnch) and then dnsopropylazodicarboxylate (147 uL, 0.75 mmol, Aldrich) with stirnng After 3 days of stimng at room temperature, the reaction mixture was added drop-wise to vigorously-stirred diethyl ether. The resultmg precipitate was isolated by filtration and washed three times with diethyl ether and dned to yield 284 mg (93%) of mPEG-O-w-phenylacetaldehyde (18) Chiral PEG-cinnarnate-N-hydroxy succmimate (NHS) compounds are generated, for example, as shown in Schemes VTO and IX Scheme VIII (Formula Removed) dihydroxydihydrucinnamate Scheme IX (Scheme Removed) a-Methy]-ß-h\droxycinnamate PEG-Dihydrourocanate-NHS compounds are also generated via a Mitsimobu reaction, as shown in Scheme X' Scheme X (Scheme Removed) PEG-Dihydrocinnarnate-NHS compounds are also generated from an aromatic alcohol as shown in Scheme XI. Scheme XI (Scheme Removed) PEG-benzofurans and PEG-mdolee are generated as shown in Schemes XII and XM. Scheme XII (Scheme Removed) CI Generation via Reaction of PEG-Amines PEG amines are reacted with alkyl halides to generate PEG-amides An example of the generation ofa PEG-amide-bicyclooctane-NHS conjugate is shown in Scheme XTV: Scheme XIV (Scheme Removed) A PEG-pnmary amine is conjugated with an aryl-halide to form a PEG-secondary amine conjugate, which is then reacted under Heck conditions (a stereospecific Palladium-catalyzed coupling of an alkene with an organic hahde or Inflate lacking sp hybridized p-hydrogens) with an Nl-IS-alkene to form the desired PEG-conjugate. The synthesis ofa pynmidine-containing conjugate is shown m Scheme XV Scheme XV (Scheme Removed) PEG-sulfonamide conjugates are also synthesized in this maimer, as shown in Scheme XVI: (Scheme Removed) D) Compounds Generated via Reaction with Ileterocycles PEG compounds are reaLted with ring- or non-ring nitrogens in heteroeycles to form reactive PEG species. Representative reactions arc shown in Schemes XVH for aminopyrrohdine and XVIH for various piperazines: Scheme XVII (Scheme Removed) EXAMPLE 2: Preparation of peptide conjugates The peptide conjugates according to the present invention can be prepared by reacting a protein with an activated PGC molecule. For example, interferon (IFN) can be reacted with a PEG-aldehyde m the presence of a reducing agent (eg., sodium cyanoborohydnde) via reductive alkylation to produce the PEG-protein conjugate, attached via an amine linkage. See, e.g.. European Patent 015431 o Bl Human IFN-ß-la was PEGylated with the following activated polyalkylene glycols of the invention: 20 kDa rnPEG-O-2-methylpTopioTialdehyde, 20 kDa mPEG-O-/'-metb.y]phenvl-O-2-mcthylpropionaldchyde, 20 kDa m_PEG-O-?n-methylphenyl-O-2-methylpropioiiflldehyde, 20 kDa mPEG-O-/j-phenylacetaldehyde, 20 kDa mPEG-O-ß-phenylpropionaldehyde, and 20 kDa mPEG-O-m-phenylacetaldehyde The PEGylated proteins were purified to homogeneity from their respective reaction mixtures and subjected to a series of characterization tests to ascertain the identity, purity, and potency of the modified proteins. A detailed description of the preparation and characterization of humanfFN-ß-la modified with 20 kDa niPEG-O-2-methylpropionaldehyde, 20 IcDa mPEG-O-TB-methylpheiiyl-O-2-meLhylpropionaldehyde, and 20 kDa mPEG-O-ß-phenylacetaldehyde follows. A) Preparation and Characterization of 20 kDa inPEG-Q-2-methyllpropionaldehyde-modifiedlFN-ß-Ia Human IFN-ß-la was PEGylated at its N-lenmnus with 20 kDa mPEG-O-2-methylpropionaldehyde The product of the reductive alkylahon chemistry used to incorporate the PEG onto the IFN-ß-la backboue resulted in the formation of an amine linkage which is extremely stable against degradation. The PEGylated IFN-ß-1 a was subjected to extensive characterization, including analysis by SDS-PAGE, size exclusion chromatography (SEC), peptide mapping, and assessment of activity m an in vitro antiviral assay The purity of the product, as measured by SDS-PAGE and SEC, was greater than 90% In the PEGylated sample there was no evidence of aggregates. Residual levels of unmodified IFN-µ-la in the product were below the limit of quantitation, but appear to represent about 1% of the product The specific activity of the PEGylated IFN-ß-la in the antiviral activity assay was reduced approximately 2-fold compared to the unmodified IFN-ß-1 a (EC50 = 32 pg/mL for 20 kDa mPEG-O-2-methylpropionaldehyde-modifiedTFN-ß-la versus EC50= 14 pg/mL for unmodified IFN-ß-1 a). The PEGylated IFN-ß-la bulk was formulated at 30 µg/mL in phosphate-buffered saline (PBS) pH 7 3, containing 14 rag/mL human serum albumin (HSA), similar to the formulation used for AVONEX® (Biogen, Cambridge. MA) which has been subjected to extensive characterization- The material was supplied as a frozen liquid which was stored at -70 °C The properties of 20 kDa mPEG-O-2-methylpropionaldehyde-modified IFN-ß-la are summarized in Table 1 Table 1. Properties of 20 kDa mPEG-O-2-methylpropionaldehydc-modified IFN-ß-la (Table Removed) 1 Preparation of 20 kDa mPEG-O-2-memylpropionaldehvde-roodified IFN-B-la. 10 mL of nonformulated AVONEX® (IFN-ß-la bulk intermediate, a clinical batch of bulk drug that passed all tests for use in humans, at 250 ug/mL in 100 mM sodium phosphate pH 7.2,200 mMNaCl) was diluted with 12 mL of 165 mM MES pH 5 0 and 50 µL of 5 N HC1 The sample was loaded onto a 300 uL SP-Sepharose FF column (Pharmacia) The column was washed with 3 x 300 ▲L of 5 mM sodium phosphate pH 5 5, 75 mM NaG, and the protein was etuted with 5 mM sodium phosphate pH 5 ei, 600 mM NaCl Ehition fractions were analyzed tor then absorbance at 280 nm and the concentration of IEN-ß-1 a in the samples estimated using an extinction coefficient of 1 51 for a 1 mg/mL solution The peak fractions were pooled to give an IFN-ß-la concentration of 3 66 mg/mL, which was subsequently diluted to 1.2 mg/mL with water To 0 8 mL of the IFN-ß-la from the diluted SP-Scpharose eluate pool, 0.5 M sodium phosphate pH 6 0 was added to 50 mM, sodium cyanoborohydride (Aldrich) was added to 5 mM, and 20 kDa mPEG-O-2-mefhylpropionaldehyde was added to 5 mg/mL The sample was incubated at room temperature for 16 h in the dark The PFGylated IFN-j3-la was purified from the reaction mixruie on a 0 5 mL SP-Sepharose FF column as follows 0.6 mL of the reaction mixture was diluted with 2.4 mL 20 mM MES pH 5 0, and loaded on to the SP-Sepharose column The column WBS washed with sodium phosphate pH 5 5, 75 mM NaCl and then the PEGylated IFN-pMa was eluted from the column with 25 mM MES pll 6 4,400 mM NaCl The PEGylated IFN-ß-1 a was further purified on a Superose 6 HR 10/30 FPLC sizing column widi 5 mM sodium phosphate pH 5.5,150 mM NaCl as the mobile phase. The sizing column (25 mL) was run at 20 mL/h and 0 5 mL fractions were collected. The elution fractions were analyzed for protein content by absorbance at 280 nm, pooled, and the protein concentration of the pool determined The PEGylated IFN-ß-la concentration is reported in IFN equivalents as the PEG muiety does not contribute to absorbance at 280 nm. Samples of the pool were removed for analysis, and the remainder was diluted to 30 µg/mL with HSA-eontaining formulation buffer, ahquoted at 0.25 mL/viaL and stored at -70 °C 2 UV spectrum of purified 20 kDa mPEG-O-2-meth.Ylpropionalderrvde-modified lEN-ß-Ia The UV spectrum (240-340 nm) of 20 kDa mPEG-O-2-methylpropionaIdehyde-modified IFN-ß-la was obtained using the pre-HSA formulated bulk sample The PEGylated sample exhibited an absorbance maximum at 27S-279 nm and an absoibance minimum at 249-250 nm, consistent with that observed for the unmodified IFN-ß-la bulk intermediate The protein concentration of the PEGylated product was estimated from the spectrum using an extinction coefficient of E2so01° = 1.51 The protein concentration of the PEGylated bulk was 0 23 mg/mL. No turbidity was present m the sample as evident by a lack of absorbance at 320 run 3 Characterization of 20 kDa mPEG-O-2-nielhvlpropionaldehvdc-modified 1FN-ß-Ia by SDS-PAGE 4 jj.g of unmodified and 20 kDa mPEG-O-2-methyIpropionaIdelryde-rnodified IFN-(i-l a were subjected to SDS-PAGE under reducing conditions on a 10-20% gradient gel The gel was stained with Coomassie brilliant blue R-250, and is shown in Figure 1 (Lane A, molecular weight markers (from top to bottom; 100 kDa, 68 kDa, 45 kDa, 27 kDa, and 18 kDa, respectively); Lane B, unmodified IFN-ß-la, Lane C, 20 kDa mPEG-O-2-methylpropionaldchyde-raodified IFN-fl-IaJ. SDS-PAGE analysis of 20 kDa mPEG-O-2-methylpropionaldehyde-modified IFN-ß-la revealed a single major band vritli an apparent mass of 55 kDa, consistent with modification by A single PFG No higher mast, forms resulting from the presence of additional PEG groups were detected In the purified, PEGylated product, unmodified TFN-ß-1 a was detected; however, the amount is below the limit of quantitation. The level of unmodified IFN-ß-la in the preparation is estimated to account tor only about I % of the total protein. 4 Characterization of 20 kDa mPEG-O-2-methylpropionaldehyde-modified IFN-ß-la by size exclusion chromatography. Unmodified and 20 kDa mPEG-O-2-methylpropionaldehyde-modified IFN-ß-la were subjected to SEC on an analytical Superose 6 HR10/30 FPLC sizing column using PBS pll 7 2 as the mobile phase The column was run at 20 rrnVh and the eluent monitored for absorbance at 2SO nm, as shown in Figure 2; Panel A. molecular weight standards (670 kDa, thyroglobuhn; 158 kDa, gamma globulin; 44 kDa, ovalbumin, 17 kDa, myoglobin, 1 3 kDa, vitamin B12), Panel B. 20 kDa mPEG-O-2-methylpropionaldehyde-modiried IFN-ß-i a, Panel C unmodified IFN-ß-1 a The 20 kDa mPEG-O-2-melhylpTopionaldehydc-niodiiied TFN-3-la eluted as a single sharp peak with an apparent molecular mass of approximately 200 kDa, consistent with the large hydrodynamic volume of the PEG No evidence of aggregates was observed Unmodified IFN-ß-la in the preparation was detected but was below the limit of quantitation Based on the Eize of the peak, the unmodified IFN-ß-la accounts for 1% or less of the product, consistent with (hat observed using SDS-PAGE 5 Analysts of 2U kDa mPEG-O-2-methylproTJionaldehvde-modified IFN-B-la by peptide mapping. The specificity of the PEGylation reaction was evaluated by peptide mapping Unmodified and 20 kDa mPEG-O-2-methylpropionaldehyde-modificd EFN-ß-1 a were digested with endoproteinase Lys-C from Achromobacter (Wako Byproducts') and the resulting cleavage products were fractionated by reverse-phase HPLC on a Vydac C1 column using a 30 mm gradient from 0 to 70% acetonitrile, in 0 1% TEA. The column eluent was monitored for absorbance at 214 nm All of the predicted peptides from the endopioteuuse Lys-C digest of IFN-ß-la have been identified previously by N-terminal sequencing and mass spectrometry (Pepmsky et al., (2001) J Pharmacology and Experimental Theiapeutics 297 1059), and, of these, only the peptide that contains the N-termmus of IFN-ß-la was altered by modification with 20 kDa mPEG-O-2-methylpropionaldehyde; as evident by its disappearance from the peptide map The mapping data therefore indicate that the PEG moiety is specifically attached to this peptide. The data lurlher indicate that the PEG modification is targeted at the N-terminus of the protein since only the N-terminal modification would result m the specific loss of this peptide B) Preparation and Characterization of 20 kDa rnPEG-Q-r»-rriethylt)lienvTQ-2-methylpTopionaldehyde-niodified ITN-B-1 a Human IFN-ß-Ia was TEGyJated at the N-rerminus with 20 kDa mPEG-O-MJ-methylphenyl-O-2-methylpropionaldehyde The product of trie reductive alkylation chemistry that was used to incorporate the PEG onto the IFN-ß-!a backbone results in the formation of an amine linkage which is extremely stable against degradation. The PEGylated IFN-ß-la was subjected to extensive characterization, including analysis by SDS-PAGE, SEC, peptide mapping, and assessment of activity in an in vitro antiviral assay. The purity of the product as measured by SDS-PAGE and SEC was greater than 95% In the PEGylated EFN-ß-la sample there was no evidence of aggregates. Residual levels of unmodified lTN-ß-la m the product were below the limit of quantitation, but appear to represent about 1% of the product. The specific activity of the PEGylated IFN-ß-la in the antiviral activity assay was reduced approximately 2-fold compared to the unmodified lFN-ß-la (EC;o = 31 pg/raL for 20 kDa mPEG-tJ'f?i-methylphenyl-O-2-methylpropionaldchyde-niod]fiedIFN-ß-la versus EC50 - 14 pg/mL for unmodified IFN-ß-la). The PEGylated IFN-ß-la bulk was formulated at 30 p.g/mL in PBS pH 7 2 containing 15 nig/mL HSA, similar lo the formulation used for AVONEX® which has been subjected to extensive characterization The material was supplied as a frozen Liquid which was stored at —70 °C The properties of 20 kDamPEG-O-/n-methylphenyl-O-2-methylpropiona]debyde-modified IFN-B-la are summarized in Table 2 Table 2- Properties of 20 kDa mPEG-O-m-methylphenyl-O-2-methylpTopionaldehyde- modified IFN-O-la (Table Removed) 1 Preparation of 20 kDa rnPEG-O-w-methylphenyl-O-2-methylpropionaldehvde-modifiedli-N-B-la 80 mL of nonformulated AVONEX® (IFN-ß-1 a bulk intermediate, a clinical batch of bulk drug that passed all tests for use m humans, at 254 )ig/mL in 100 mM sodium phosphate pH 7 2, 200 mM NaCl) was diluted with 96 mL of 165 mM MES pH 5 0, and 400 uL of 5 N HC1 The sample was loaded onto a 1 2 mL SP-Sepharose FF column (Pharmacia) The column was washed with 6 5 mL of 5 mM sodium phosphate pH 5 5, 75 mM NaCl, and the protein was eluted with 5 mM sodium phosphate pH 5 5, 600 mM Nad Elution fractions were analyzed [or their absorbance at 280 nm and the concentration of IFN-ß-la in the samples was estimated using an extinction coefficient of 1.51 for a 1 mg/mL solution The peak fractions were pooled to give an IFN-ß-la concentration of 4.4 nig/mL To 2 36 mL of the 4 4 mg/mL IFN-ß-la from the SP-Sepharose eluate pool, 0,5 M sodium phosphate pH 6 0 was added to 50 mM, sodium cyonoborohydnde (Aldrich) was added to 5 mM, and 20 kDa mPEG-O-TJi-methylphenyl-O-2-methylpropionaldehyde, was added to 10 mg/mL. The sample was incubated at room temperature for 21 h in the dark The PEGylated IFN-ß-1 a was purified from the reaction mixture on a 8 0 mL SP-Sepharose FF column as follows. 9.44 mL of reaction mixture was diluted with 37.7 mL of 20 mM MES pH 5 0, and loaded onto the SP-Sepharose column The column was washed with sodium phosphate pH 5 5, 75 mM NaCl and then the PEGylated IFN-ß-1 a was eluted from the column with 25 mM MES pH 6 4, 400 mM NaCl. The PEGylated IFN-ß-la was further purified on a Superose 6 IIR 10/30 FPLC sizing column with 5 mM sodium phosphate pH 5.5, 150 mM NaCl as the mobile phase. The sizing column (25 mL) was run at 24 mL/h and 0.25 mL fractions were collected. The elution fractions were analyzed for protein content by SDS-PAGE, pooled, and the protein concentration of the pool determined The PEGylated IFN-ß-la concentrabon is reported in IFN equh alents after adjusting for the contribution of the PEG to the absorbance at 2SO nm using an extinction coefficient of 2 for a 1 mg/mL solution of the PEGylated IFN-ß-1 a. Samples of the pool were removed for analysis, and the remainder was diluted to 30 p-g/mL with HSA-containing formulation buffer, ahquoted at 0 25 mL/vial, and stored at -70 °C. 2. UV spectrum of punfied 20 kDa rnPEG-O-m-methylphcnyl-O-2-methylpropionaldehyde-modified IFN-O-1 a The UV spectrum (240-340 ran) of 20 kDa mPEG-O-m-methylphenyl-O-2-methylpropionaldehyde-modified IFN-ß-la was obtained using the pre-HSA-formulated bulk sample. The PEGylated sample exhibited an absorbance maximum at 278-279 nm and an absorbance minimum at 249-250 run, consistent with that observed for the unmodified IFN-ß-1 a bulk intermediate The protein concentration of the PEGylated product was estimated from the spectrum using an extinction coefficient of 28001% = 2.0. The protein concentration of the PEGylated bulk was 0 42 mg/mL No turbidity was present in the sample as evident by the lack of absorbance at 320 nm. 3 Characterization of 20 kDa mPEG-Q-m-methylphenvl-O-2-methylpropionaldehvde-modified lFN-ß-la by SDS-PAGE 2 1 µg of 20 kDa niPEG-O-™-methyIphenyh-O2-methylpropionaldehyde-modified IFN-ß-la was subjected to SDS-PAGE under reducing conditions on a 4-20% giadient gel. The gel was stained with Coomassie brilliant blue R-250 SDS-PAGE analysis of 20 kDamPEG-O-m-melhylphenyl-O-2-methylpropionaldehyde-modified IFN-ß-1 a revealed a single major band with an apparent mass of 55 kDa consistent with modification by a single PEG In the purified PEGylated product unmodified IFN-ß-la was detected, however, the amount is below the limit of quantitation. It is estimated that the level of unmodified IFN-ß-la in the preparation accounts for only about 1% of the total protein 4 Characterization of 20 kDa mPEG-O-m-methybhenyl-O-2-mcthvlpropionaldehyde-modified IFN-ß-1 a by size exclusion chromatography. 20 kDa mPEG-O-m-methylphenyl-O-2-methylpropiorialdehyde-modified IFN-ß-la was subjected to SEC on an analytical Superose 6 HR10/30 FPLC sizing column using PBS pH 7.0 as the mobile phase The column was run at 24 mL/h and the eluent was monitored for absorbance at 280 nm. The PEGylated IFN-ß-1 a eluted as a single sharp peak with no evidence of aggregates (Figure 3) 5 Analysis of 20 kDa mPEG-O-m-methylphenyl-O-2-methyrpropionaldehvde-modified IFN-ß-1 a by peptide mapping. The specificity oft he PEGylalion reaction was evaluated by peptide mapping 13.3 ug of unmodified and 20 kDa mPEG-O-m-melhylphenyl-O-2-methylpropionaldehyde-modified IFN-ß-la were digested with 20% (w/w) of endoproteinase Lys-C from Achromobacter ("Wako Bioproducts) in PBS containing 5 mM DTT, 1 mM EDTA, at pH 7 6, at room temperature for 30 h (final volume - 100 µL) 4 µL of 1 M DTT and 100 µX of 8 M urea were then added and the samples incubated for 1 h at room temperature The peptides were separated by reverse-phase HPLC on a Vydac Cl18 column (214TP51) using a 70 min gradient from 0-63% aoetonitnle, m 0 1 % TFA, followed by a 10 nun gradient from 63-80% acetomtnle, in 0.1% TFA The column cluent was monitored for absorbance at 214 nm All of the predicted peptides from the endoproteinase Lys-C digest of IFN-ß-l a have been identified previously by N-terminal sequencing and mass spectrometry (Pepinsky et al., (2001) J Pharmacology and Experimental Therapeutics 297 1059), and, of these, only the peptide that contains the N-tcrmmut. of IFN-ß-1 a w as altered by modification with 20 kDa mPEG-O-m-methylphenyl-O-2-methylpTopionaldehyde, as evident by its disappearance from the map. The mapping data therefore indicate that the PEG moiety is specifically attached to tins peptide The data further indicate that the PEG modification is targeted at the N-terrninus of the protem since only the N-terminal modification would result in the specific loss of this peptide C) Preparation and Chaiacterization of 20 kDn mPEG-O-ß-phenvlacetaldehyde-modified IFN-ß-la Human IFN-ß-la was PEGylated at the N-terrninus with 20 kDa mPEG-O-p-phcnylacetaldehyde The product of the reductive alkylation chemistry that was used to incorporate the PEG onto the IFN-ß-la backbone results* ui the formation of an amine linkage which is extremely stable against degradation. The PEGylated IFN-ß-1 a was subjected to extensive characterization, including analysis by SDS-PAGE, SEC, peptide mapping, and assessment of activil-y in an in vitro antiviral assay The punty of the product as measured by SDS-PAGE and SEC was greater than 95%. In the PEGylated IFN-Q-la sample there was no evidence of aggregates Residual levels of unmodified IFN-ß-la in the product were below the limit of quantitation; but appear to represent about 1 % of the product. In a stability test, no aggregation or degradation of 20 kDa mPEG-O-/>-phenylacetaldehyde-modified TFN(i-la was evident in Tris-buffer pH 7.4, following an incubation at J 7 °C for up to 7 days. The specific activity of the PEGylated IFN-O-la in the antiviral activity assay was reduced approximately 2-fold compared to the unmodified IFN-ß-la (EC50 = 31 pg/mL for 20 kDa mPEG-O-ß-phenylacetaldehyde-modified TFN-tf-la versus ECso - 14 pg/mL for unmodified IFN-ß-la). The PEGylated IFN-ß-la bulk was formulated at 30 (ig/mL m PBS pH 7 3 containing 14 mg/mL HSA. similar to the fonnulation used for AVONEX® which has been subjected to extensive characterization The material was supplied as a frozen liquid which was stored at -70 °C The properties of 20 kDa mPEG-O-ß-phenylacetaldehyde-modified IFN-ß-la are summarized in Tabic 3' Table3. Properties of 20kDa mPEG-O-/>-phenylacetaldehyde-rnodified IFN-ß-la (Table Removed) 1 Preparation of 20 kDa mPEG-O-ß-pherjvlacetaldehvde-modilied IFN-ß-la 20 mL of nonformulated AVONEX$ (EFN-ß-1 a bulk intermediate, a clinical batch of bulk drug that passed all tests tor use m humans, at 250 Hg/mL in 100 mM sodium phosphate pH 7 2,200 mM NaCl) was diluted with 24 mL of 165 mM MES pH 5 0,100 u.L of 5 N HC1, and 24 mL water. The sample was loaded onto a 600 uL SP-Sephamse FF column (Pharmacia). The column was washed with 2 x 900 uL of 5 mM sodium phosphate pH 5.5, 75 mM NaCl, and the protein was eluted with 5 mM sodium phosphate pH 5 5, 600 mM NaCl. Elution fractions were analyzed for then absurbance at 280 ran and the concentration of IFN-ß-la in the samples was estimated using an extinction coefficient of 1.5.1 for a 1 mg/mL solution The peak fractions were pooled tu give an IFN-ß-la concentration of 2 3 mg/mL. To 1.2 mL of the IFN-p-1 a from the SP-Sepharosc eluate pool, 0.5 M sodium phosphate pH 6.0 was added to 50 mM, sodium cyanoborohydride f Aldrich) was added to 5 mM, and 20 kDa mPKG-O-ß-phenylacetaldehyde, was added to 10 mg/mL. The sample was incubated at room temperature for 18 h in the dark The PEGylated IFN-ß-1 a was purified from the reaction mixture on a 0 75 mL SP-Sepharose FF column as follows: 1.5 mL of reaction mixture was diluted with 7 5 mL of 20 mM MES pH 5.0, 7.5 mL water, and 5 pL 5 N HO, and loaded onto the SP-Sepharosc column The column was washed with sodium phosphate pH 5,5, 75 mM NaCl and then the PEGylated IFN-ß-la was eluted from the column with 20 mM MES pH 6 0, 600 mM NaCl. The PEGylated IFN-ß-1 a was further purified on a Superose 6 HR 10/30 FPLC sizing column with 5 mM sodium phosphate pH 5 5, 150 mM NaCl as the mobile phase The sizing column (25 mL) vvas run at 20 mL/h and 0 5 mL fiactions were collected The elution fractions were analyzed for protein content by absorbance at 280 nm, pooled, and the protein concentration of the pool determined. The PEGylnted IFN-ß-la concentration is reported in IFN equivalents after adjusting for the contribution of the PEG (20 kDa mPEG-O-p-phenylacetaldehyde has an extinction coefficient at 2SO nm of 0.5 for a 1 mg/mL solution) to the absorbance at 280 nm usmg an extinction coefficient of 2 for a 1 mg/mL solution of the PEGylated IFN-ß-la Samples of the pool were removed for analysis, and the remainder was diluted to 30 µg/mL with HSA-con taming formulation buffer, aliquoted at 0.25 mL/vial, and stored at -70 °C 2 UV spectrum of purified 20 kDa rnPEG-O-ß-phenvlacetaldehvde-modified IFN-3-la. The UV spectrum (240-340 nm) of 20 kDa mPECi-O-ß-phenylacetaldehyde-modified IFN-ß-la was obtained using the pre-HSA-fommlated bulk sample The PEGylated sample exhibited an absorbance maximum at 278-279 nm and an absorbance minimum at 249-250 nm, consistent with that observed for the unmodified LFN-ß-1 a bulk intermediate The protein concentration of the PEGylated product was estimated from the spectrum using an extinction coefficient of B2so° ^ = 2.0. The protein concentration of the PEGylated bulk was 0 10 mg/mL No tufbidity w as present in the sample as evident by the lack of absorbance at 320 nm 3. Characterization of 20 kDa mPEG-Q-ß-phenvlacetaldefryde-modified IFN-O-la by SDS-PAGE 2.5 fig of unmodified and 20 kDa inPEG-O-_p-phenylacetaldehyde-modified IFN-ß-la were subjected to SDS-PAGE under reducing conditions on a 10-20% gradient gel The gel was stained with Coomassie brilliant blue R-250, and is shown in Figure 4 (Lane A. 20 kDa mPEG-O-ß-phenylacetaldehydc-modified IFN-ß-ia, Lane B: unmodified IFN-ß-la; Lane C: molecular weight markers (from top to bottom, 100 kDa, 68 kDa, 45 kDa, 27 kDa, and 18 kDa, respectively)). SDS-PAGE analysis of 20 kDa mPEG-O-^-plienylacetaldehyde-modifled IFN-ß-1 a revealed a single major band with an apparent mass of 5 5 kDa consistent with modification by a single PEG No higher mass forms resulting from the presence of additional PEG groups were detected. In the purified PEGylated product unmodified IFN-ß-la was detected; however, the amount is below the limit of quantitation. It is estimated that the level of unmodified IFN-ß-la in the preparation accounts for only about 1% of the total protein. 4 Characterization of 20 kDa mPEG-O-ß-phenylacetaldehyde-modified IFN-B-la by size exclusion chromatography. 20 kDa mPEG-O-ß-phenylacetaldehyde-modified IFN-ß-la was subjected to SEC on an analytical Superose 6 HP10/30 FPLC sizing column using PBS pH 7 2 as the mobile phase The column was run at 20 mL/h and the eluent was monitored for absorbance at 280 run, as shown in FigUTe 5 Panel A molecular weight standards (670 kDa, thyroglobulin, 158 kDa, gamma globulin; 44 kDa, ovalbumin, 17 kDa, myoglobin; 1 3 kDa, vitamin B12); Panel B 20 kDa mPEG-O/7-phenylacctaldehyde-modificd IFN-ß-la. The PEGy fated IFN-ß-la eluted as a single sharp peak with an apparent molecular mass of approximately 200 kDa consistent with the large hydrodynamic volume of the PEG No evidence of aggregates was observed Unmodified IFN-ß-la in the preparation was detected but was below the limit of quantitation Based on the size of the peak, the unmodified IFN-B-la accounts for 1% or less of the product, consistent with that observed using SDS-PAGE 5 Analysis of 20 kDa mPEG-Q-ß-phenvlacetaldehyde-modificd IFN-B-la by peptide mapping The specificity of the PEGylation reaction was evaluated by peptide mapping Unmodified and 20 kDa mPEG-O-ß-phenylacctaldehyde-modified IFN-ß-1 a were digested with cndoproteinase Lys-C from Achromobacter (Wako Biopraducts) and the resulting cleavage pnnlucts were fractionated by reverse-phase HPLC on a Vydac C4 column using a 30 mm gradient from 0 to 70% acetomrnle, raO 1% TFA The column elueni was monitored for absorbance at 214 run All of the predicted peptides from the endoproteinase Lys-C digest of IFN-ß-la have been identified previously by N-terminal sequencing and mass spectrometry (Pepinsky et al., (2001) J Pharmacology and Experimental Therapeutics 297-1059), and, of these, only the peptide that contains the N-teiminus of IFN-ß-la was altered by modification with 20 kDa mPEG-O-jD-phcnylacetaldehyde; as evident by its disappearance from the map. The mapping data therefore indicate that the PEG moiety is specifically attached to this peptide The data further indicate that the PEG modification is targeted at the N-terminus of the protein since only the N-terminal modification would result in the specific loss of this peptide. 6 Stability of 20 kDa mPEG-O-ß-phenylacelalderryde-modified IFN-B-la. To test the stability of 20 kDa mPEG-ß-phenylacetaldehyde-modified IFN-ß-la, samples were diluted to 0,1 pg/rnL with 100 mM Tns-HCl buffer, pH 7 4, and were then incubated at 37 CC for up to 7 days. 20 |iL of sample (2 fig) was removed at days 0, 2, 5, and 7, and analyzed by SDS- PAGR under reducing conditions, as shown in Figure 6 Lane A molecular weight markers (from top to bottom, 100 kDa, 68 kDa, 45 kDa, 27 kDa, 18 kDa, and 15 kDa, respectively); Lanes B, C, D, and E mPEG-O-p-phenylacetaldehyde-modified IFN-ß-la removed at day C, 2, 5, and 7, respectively. No evidence of aggregation or degradation of PEGylated lFN-O-la was observed even after 7 days at 37 °C EXAMPLE 3. Specific activity of PEGylated human IFN-ß-la in an in vitro antiviral assay The specific antiviral activity of PEGylated IFN-ß-la samples was tested on human lung carcinoma cells (A549 cells) that had been exposed to encepbalomyocarditis (EMC) virus>, and using the metabolic dye 2,^-bis[2-Methoxy-4-nitro-5-s>ulfo-phenyl]-2II-tetrazolium-5-carboxyanilide (MTT; M-5655, Sigma. St Louis, MO) as a measure of metabolically-active cells remaining after exposure to the virus. Briefly, A549 cells were pretieated for 24 h with either unmodified or PEGylated IFN-ß-la (starting at 66 7 pg>mL and diluting serially 1.5-fold to 0 8 pg/rnL) prior to challenge wilh virus. The cells were then challenged for 2 days with EMC virus at a dilution that resulted in complete cell killing in the absence of iFN Plates were then developed with MTT. A stock solution of MTT was prepared at 5 mg/mL in PBS and sterile-filtered, and 50 pL of this solution was diluted into cell cultures (100 pJL per well) Following incubation at room temperature for 30-60 nun, the MTT/media solution was discarded, cells were washed with 100 \iL PBS, and finally the metabolized dye was solubilized with 100 fiL 1.2 N HCl in lbopropanol. Viable cells (as determined by the presence of the dye) were quantified by absorbance at 450 ran Data were analyzed by plotting absorbance agjmbt the concentration of IFN-(V la, and the activity of IFN-ß-la was defined as the concentration at which 50% of the cells wrere killed ; e the 50% cytopathic effect (ECso") or 50% maximum OD^so The assay was performed eight times for unmodified IFN-ß-la and three to four times with the various PEGylated IFN-ß-la samples For each assay, duplicate data points for each protein concentration were obtained. Representative plols of cell viability versus the concentration of unmodified or PEGylated IFN-ß-1 a are shown in Figures 7A and 7B In Figure 7A, the symbols are as follows, unmodified IFN-ß-la (O). 20 kDa mPEG-O-2- methylpropionaldehyde-moditied IFN-ß-la (a), 20 kDa mPEG-O-ß-methylphenyl-O-2- methylpropionaldehyde-modified IFN-ß-la (A), and 20 kDa rnPEG-O-w-methylphenyl-O-2- methylpropicinaldehyde-mudified IFN-ß-la (o) In Figure 7B, the symbols are as follows- unmodified IFN-(i-la (Q), 20 kDa mTFG-O-ß-phenylacctaldehyde-modified IFN-ß-Ia (□), 20 kDa mPEG-O-p-pheny]propionatf ehyde-modified IFN-ß-la (A), and 20 kDa mPEG-O-m- phenykcetaldehydc-modified IFN-ß-la (o) The EC50 values (the concentration at half-maximal viral protection) for IFN-ß-la modified with 20 kDa mPEG-O-2-methylpropionaldehyde, 20 kDa mPEG-O-ß-methylphenyl-O-2-Tnethylpropionaldehydc, 20 kDa mPEG-O-in-methylphenyI-O-2-rncthylpropioiialdehyde, 20 kDa mPEG-O-p-phenylacetaldehyde, 20 kDa iuPEG-O-p-phenylpropionaldehyde, and 20 kDa mPEG-O-m-phenylacetaldehyde are shiown in Table 4. All PEGylated TFNs-ß-la were modified and punfied to homogeneity essentially as described for 20 kDa mPEG-O-2-methylpropionaldehyde-modified IFN-ß-la, 20 kDa niPLG-O-/n-methylphenyl-O-2-methylplpopronaldehyde-modified IFN-ß-la, and 20 kDa roFEG-O-ß-phenylacetaldehyde-modified IFN-ß-la as described above Table 4. Specific antiviral activity of unmodified and PEGylated IFNs-ß-la (Table Removed) EXAMPLE 4. Pharmacokinetics of intravenously-administered unmodified and PEGylated IFNs-ß-la in rats Canulated female Lewis rats were injected intravenously with either SO p-gftg of unmodified IFN-ß-la or 24 ^g/kg of the following PEGylated IFNs-ß-la; 20 kDa mPEG-O-2-methylpropionaldehyde-modrfied IFN-ß-la, 20 kDa mPEG-O-/;-methylphenyl-()-2-methylpropionaldehyde-modiHed IFN-ß-la, 20 kDa mPEG-O-/NphenylacetaJdehyde-inodified IFN-ß-la. 20 kDa mPEG-O-yj-phenylpropionaldehyde-modifiedIFN-ß-la. 20kDa mPEG-O-/»-phenylacetaldehyde-modified IFN-ß-la, and 20 kDa mPEG-O-m-methylphenyl-O-2-methylpropionaldehyde-modified IFN-ß-la. Both tlie unmodified and PEGylated proteins were formulated tn the presence of 14-15 mg/raL HSA as a earner. For the unmodified protein, blood (0.2 ml_) was obtained via the canula at different time points; immediately prior to administration, and at 0.083, 0 25,0.5,1 25.3, and 5 hours post-administration For the PEGylated proteins, blood (0 2 mL) was obtained via the canula immediately prior to administration, and at 0.083, 025, 0.5,1 25,3, 24, 48, and 72 hpost-administration Whole blood was collected into serum separator tubes (Beckton Dickinson No. 365956) and incubated at room temperature for 60 mm to allow for clotting. The clotted blood was centriluged for 10 min at 4 °C, and the serum removed and stored at -70 °C until the time of assay The serum samples were then thawed and tested in antiviral assays. The serum samples were diluted 1 50 into serum-containing medium (Dulbecco's Modified Eagles Medium containing 10% (v/v) fetal bovine serum, 100 U each of penicillin and streptomycin, and 2 mM L-glutnmine) and tested in antiviral assays Samples were titrated into designated wells of a 96 well tissue culture plate containing human lung carcinoma cells (A549, #CCL-185, ATCC, Rockville, MD). Dilutions of a standard (66 7.44 4, 29.6. 19 8, 13.2, 3 8, 5 9, 3 9, 2 6, 1 7, 1 2, and 0.8 pg/mL of the same form of IFN-ß-la administered to the rat) and of three serum samples were assayed on each plate The A549 cells were pietreated with diluted scrum samples for 24 h prior to challenge with encephalomyelocarditis (EMC) virus. Following a 2 day incubation with virus, viable cells were stained with a solution of MTT (at 5 mg/mL in phosphate buffer) for 1 h, washed with phosphate buffer, and solubilized with 1.2 N HC1 in isopropanol. The wells were then read at 450 nm Standard curves of the unmodified or PEGylated IFN-(3-l a were generated for each plate and used to determine the amount of unmodified or PEGylated IFN-ß-la in each test sample Pharmacokinetic parameters were then calculated using non-compartmental analysis with WinNonLm version 3.0 or 3 3 software, Figure 8A shows the concentration versus time plots for unmodified IFN-ß-la (upper panel) and IFN-ß-la modified with 20 kDa mPEG-O-2-methylpropionaldehyde (lower panel), and Figure 8B shows the concentration versus time plots for IFN-ß-la modified with 20 kDa mPEG-O-^'methylphenyl-O-2-methylpropionaldehyde (upper panel) and 20 kDa mPEG-O-ß-phenylacetaldehydc (lower panel). Data points are averages from measurements from 3 rats. Table 5 shows the pharmacokinetic parameters Croax (maximal observed concentration), ti/z (elimination half-life) AUC (area under the curve), Vss (distribution volume at steady state), clearance rate, and MRT (mean residence time) for unmodified IFN-ß-la and these forms of PEGylated fFN-ß-1 a. The data shown in Figures SA and 8B and in Table 5 were obtained m the same study. Figure 9A shows the cnncentTdiion versus time plots for unmodi ried IFN-ß-la (upper panel) and IFN-3-1 a modified with 20 kDa mPEG-O-ß-phenylpropionaluehyde (lower panel). Data points arc averages from measurements from 2 rats Figure 9B shows the concentration versus time plots for IFN-ß-la modified with 20 kDa mPEG-O/n-phenylacetaldchyde (upper panel) and 20 kDa mPEG-O-w-memylphenyl-O-2-methylpropionaldehyde (lower panel). Data pomts are averages from measurements from 3 rats Table 6 shows the pharmacokinetic parameters for unmodified IFN-ß-la and these forms of PEGylated IFN-ß-la The data shown in Figures 9A and 9B and in Table 6 were obtained in the same study; independent from the data shown m Figures 8 \ and 8B, and in Table 5 As is clear from the data shown in Figures 8 A, SB, 9A, and 9B, and in Tables 5 and 6, PEGylation of IFN-ß-la with the PEG molecules of the invention improves the pharmacokinetic properties of IFN-ß-la. In all cases, the PEGylated proteins were cleared less rapidly than unmodified IFN-ß-la, resulting in clearance rates of 3.9-8.3 mL/h/kgas compared to 160-170 mL/h/kg for the unmodified protein. As a consequence of the reduced clearance rates, the mean residence time (MRT) increased from approximately 1 h for the unmodified protein to 4.S-7 6 h for the PEGylated proteins. Similarly, the elimination half-life (t^) increased from approximately 1 h for the unmodified protein to 5.2-13 h for the PEGylated proteins. The area under the curve (AUC) values were also significantly increased upon PEGylation of IFN-[3-la For unmodified IFN-fi la, the AUC was approximately 0.5 u.g»h/mL while for the PEGylated proteins the AUC values ranged from approximately 3 to 6 p.g*h/mL, despite the fact that the PEGylated proteins were dosed at a level 3.3-fold lower than the unmodified protein. For the maximal observed concentration (C^), the values were generally higher for unmodified IFN-ß-la than for the PEGylated proteins, reflecting the lower dose of the modified proteins administered. For the volume of distribution at steady state (Vss), the values for all the PEGylated proteins were lower than for unmodified TFN-ß-la, indicating a restnbtion in their ability to exit the central blood compartment Table 5: Pharmacokinetic parameters for unmodified IFN-ß-la, 20 kDa mPEG-O-2-methylpropionaldehyde-niodified IFN-ß-la, 20 kDa mPFG-O-p-niethylphenyl-O-2-methylpropionaldehyde-modified IFN-ß-la, and 20 kDa mPEG-O-p-phenylacetaldehyde-modjfied IFN-ß-la following intravenous administration in ratsa (Table Removed) *The pliarmacotanetic data for the unmodified and PEG>lated IFN5-ß-1 a shown were obtained ra the same study Table 6: Pharmacokinetic parameteis for unmodified IFN-ß-la, 20 kDa mPEG-Q-ß-phenylpropionaldehydc-modified TFN-ß-la, 20 kDa mPEG-O-nj-phenylacetaldehyde-modified IFN-ß-la, and20kDa mPEG-O-m-methylphenyl-O-2-methylpropionaldehyde-modified IFN-ß-la following intravenous administration m Tals1* (Table Removed) The pharmacokinetic data for the unmodified and PEG^latcd IFNs-P~l a shown were obtained in Ihe lame study EXAMPLE 5: Comparative pharmacokinetics and pharmacodynamics of unmodified and PEGylated human IFN-B-la in non-human primates Single and Tepeat dose comparative studies are conducted with unmodified and PEGylated IFN-ß-la to determine their relative stability and activity m non-human primates. In these studies, the pharmacokinetics and pharmacodynamics of the PEGylated IFN-ß-la conjugates is compared to that of unmodified TFN-ß-la and leasonable inferences can he extended to humans Animals and Methods Study 1 (repeat dose) This 15 a parallel group, repeat dose study to evaluate the comparative pharmacokinetics and pharmacodynamics of unmodified and PEGylated IFN-ß-la. Healthy primates (e.g., rhesus monkeys) are used for this study. Prior to dosing, JII animals are evaluated for signs of ill healtli by a laboratory animal vetenninan on two occasions within 14 days prior to te.st article administration; one evaluation must be within 24 h prior to the first test article administration. Only healthy animals receive the test article. Evaluations include a general physical examination and pre-dose blood draws for baseline clinical pathology and baseline antibody level to IFN-J5-1 J. All animals are weighed and body temperatures are recorded within 24 h prior to test article administrations Twelve subjects aie enrolled and assigned to groups of three to receive 1 x 106 U/kg of unmodified or PEGylated IFN-B-la, but otherwise identical IFN-f5-1 a Administration is by either the subcutaneous (SC) or intravenous (TV) routes. Six male animals receive test article by the IV route (3 per treatment) and another 6 male animals receive test article by the SC route (3 per treatment), All animals must be naive to IFN-P treatment Each animal is dosed on two occasions, the doses are separated by four weeks The dose volume is 1 0 mL/kg Blood is drawn for pharmacokinetic testing at 0, 0 083, 0 25, 0 5,1,1 5,2,4,6, S, 12,24,48, 72, and at 96 hours following each injection Blood samples for measurement of the IFN-induced biological response marker, serum neoptenn, are drawn at 0,24,48,72,96,168,336, and at 504 h following administration of study drug, Evaluations during the studypenod include clinical observations performed 30 min and 1 h post-dose for signs of toxicity. Daily cage-side observations aie performed and general appearance, signs of toxicity, discomfort, and changes in behavior are recorded Body weights and body temperatures are recorded at regular intervals through 21 days post-dose Study 2 (single dose1) Tins is d parallel group, single dose study to evaluate the comparative pharmacokinetics and pharmacodynamics a f unmodified and PEGylated IFN-ß-1 a Healthy primates (e g. rhesus monkeys) are used for tins, study. Prior to dosing, all animals are evaluated for signs of ill health by a laboratory animal veterinarian on two occasions within 14 days pnor to test article administration, one evaluation must be within 24 h pnor to the first test article ddmmibtratiun, Only healthy animals receive the test article Evaluations include a genera] physical examination and prc-dose blood draws for baseline clinical pathology and baseline antibody level to IFN-ß-la All animals are weighed and body tempera Lures are recorded within 24 h pnor to test article administrations Twenty subjects are enrolled and asfaigned to one of live groups of four animals (2 male and 2 female per group) to receive either 1 x 10s U/kg of unmodified or PEGylated IFN-ß- la intramuscularly (IM), or 2 x 105 U/kg, 1 x 106 U/kg, or 5 ~ Assay Methods Levels of LFN-ß-1 a m serum are quantitated using a cytopathic effect (CPE) bioassay. The CPE assay measures levels of IFN-mediated antiviral activity The level of antiviral activity m a sample reflects the number of molecules of active IFN contained in that sample al the time the blood is drawn. This approach has been the standard method to assess the pharmacokinetics of IFN-p. The CPE assay detects the ability of IFN-p to protect human lung carcinoma cells (A549, #CCL-185, ATCC, Rockville, MD) from cytotoxicity due to encephalomyocarditis (EMC) virus The cells are preincubatcd for ] 5-20 h with serum samples to allow the induction and synthesis of IFN-inducible proteins that are responsible for the antiviral response EMC virus is then added and incubated for a further 30 h before assessment of cytotoxicity is made using a crystal violet stain. An internal IFN-ß standard as well as a PEGylated LFN-ß-la internal standard is tested concurrently with samples on each assay plate This standard is calibrated against a natural human fibroblast IFN reference standard (WHO Second International Standard for Interferon, Human Fibroblast, Gb-23-902-53) Each assay plate also includes cell growth control wells containing neither IFN-(i of any kind nor EMC, and virus control wells that contain cells and EMC but no IFN-|3. Control plates containing the standard and samples are also prepared to determine the effect, if any, of the samples on cell growth. These plates are stained without the addition of virus Samples and standards are tested in duplicate on each of two replicate assay plates, yielding four data points per sample. The geometric mean concentration of the four replicates is reported. The limit of detection in this assay is 10 U/mL. Serum concentrations of neoptenn are determined at the clinical pharmacology unit using commercially-available assays. Serum concentrations of 2'-5'-OAS are determined at a contract laboratory using a validated cominercialty-available assay Pharmacokinetic and Statistical Methods Rstrip™ software (MicroMath, Inc , Salt Lake City. UT) is used to lit data to pharmacokinetic models Geometric mean concentrations are plotted by time for each group Since assay results are expressed in dilutions, geometric means are considered more appropriate than arithmetic means Serum IFN levels arc adjusted for baseline values and non-detectable serum concentrations are set to 5 U/mL, which represent"? one-half the lower limit of detection For IV infusion data, a two compartment IV infusion model is lit to the detectable serum concentrations for each subject, and the SC data are fit to a two compartment injection model. The iollowmg pharmacokinetic parameters are calculated (I) observed peak concentratioiij Cm« (IJ/niL). (li) area under the curve from 0 to 48 h, AUC (U x h/mL) using the trapezoidal rule, (ni) elimination half-life (h): and, from IV infusion data (if IV is employed): (iv) distribution half-life (h), (v) clearance (mL/h/kg) (vi) apparent volume of distribution, Vd (ml/kg) WinNonlin (Version 1.0, Scientific Consulting Inc , Apex, NC) software is used to calculate the elimination half-lives after IV and SC injection For neoptcrin and 2'-5'-OAS, arithmetic means by time are presented for each group Emax, the maximum change from baselme, is calculated Cmax AUC, and Emax are submitted to a one-way analysis of variance to compare dosmg groups. Cmax and AUC are loganthmically-transformed pnor to analysis; geometric means are reported EXAMPLE 6: Anti-angiogenk effects of PEGylated human IFN-ß-la: the ability of PEGylattd IFN-ß-la to inhibit endothelial cell proliferation in vitro Human venous endothelial cells (Cell Systems, Cat # 2V0-P75) and human dermal microvascular endothelial cells (Cell Systems, Cat # 2M1-C25) are maintained in culture with CS-C Medium Kit (Cell Systems, Cat. # 4Z0-500). 24 h pnoi to the experiment, cells are trypsinized, and resuspended in assay medium, 90% Ml99 and 10% fetal bovine serum (FBS), and are adjusted to desired cell density. Cells are then plated onto gelatin-coated 24 or 96 well plates, either at 12, 500 cellb/well or 2, 000 cells/well, respectively. Alter overnight incubation, the assay medium is replaced with fresh medium containing 20 ng/mL of human recombinant basic Fibroblast Growth Factor (bFGF) (Becton Dickinson, Cat # 40060) and various concentrations of unmodified or PEGylated IFN-ß-la of the invention or positive control (endostatin can be used as a positive control, as could an antibody to bFGF) are added. The final volume is adjusted to 0 5 mL in the 24 well plate or 0.2 mL in the 96 well plate. After 72 h, cells are trypsinized for Coulter counting, frozen tor CyQuant fluorescence reading, or labeled with [3H]-thymidine This in vitro assay tests the PEGylated human IFN-fi-la molecules of the invention for effects on endothelial cell proliferation which may be indicative of anh-angiogenic effects m vivo. See O'Reilly, et a!, Cell 88: 277-285 (1997). EXAMPLE 7 In vivo models to test anti-angiogenic and neovascularization effects of PEGylated human IFN-ß-la and PEGylated rodent IFNs-p Unmodified LFN-ß-la and 20 kDa mPEG-O-2-methylpropionaIdehyde-modified IFN-p-la were tested for their ability to inhibit the formation of radially-oriented vessels entering the periphery of SK-MEL-1 human malignant melanoma tumors in athymic nude homozygous (iculnu) mice. SK-MEL-1 cells were grown m culture to 80% confluency, and then 2x10" cells inoculated mfradermally (0.1 mL volume on day 0) mto the flank in the mid-axillary line in three week old athymic nude homozygous (nu/nu) NCR mice (Taconic, Germantown, NY) 24 hours later (day 1), groupt. of ihiee mice each received the following subcutaneous doses of vehicle control, unmodified IFN-ß-la, or 20 kDa mPEG-O-2-methylpropionaldehyde-modified IFN-ß-la Group A- 0 1 mL of 45 6 mg/mL human serum albumin (vehicle control) once on day 1 only Group B- 0 1 mL of 45 6 mg/mL human serum albumin containing 1 MU (5 µg) of unmodified IFN-ß-la daily on days 1-9 inclusive Group C 0 1 mL of 45 6 mg/mL human serum albumin containing 1 MU units (10 µg) of 20 kDamPEG-O-Z-methylpropionaldehyde-niodified IFN-ß-la once on day 1 only Group D. 0 1 mL of 45.6 mg/mL human scrum albumin (vehicle control) daily on days 1-9 inclusive Mice were sacrificed on day 10 (Avertm, 0 5 mL mtrapentoneally) and the tumor inoculation sile assessed for neovascularization, measured by an observer blind as to treatment group. Vessels were counted under fixed magnification under a dissecting microscope. Every radially-oncnted vessel entenng the penphery of the tumor was scored as a single vessel Each group consisted of three mice As shown in Figure 10, a single administration of ] MU of 20 kDa mPEG-O-2-methylpropiuruldehyde-modified IFN-ß-la (group O was as effective at reducing the number of neovesscis as daily administration of 1 MU of unmodified IFN-ß-la (group B) However, the effect of the 20 kDa mPEG-O-2-methylpropionaldehyde-modified IFN-ß-la is more pronounced when considering that daily administration of the vehicle alone had some inhibitory effect (compare group A, vehicle given once, with group D, vehicle given daily). A vancty of otheT models have also been developed which can be used to test the anti-angiogenic and anti-neovasculanzation effects of the PEGylated molecules of the invention Some of these models have been described in United States Patents 5,733,876 (Mar 31,1998. "Method of inhibiting angiogenesis") and 5,135,919 (Aug 4, 1992: "Method and a pharmaceutical composition for the inhibition of angiogenesis") Other assays include the shell-less chorioallantoic membrane (CAM) assay of Taylor and Folkman, Nature 297.307 (1982) andCnimetal .Science 230.1375 (1985), the mouse dorsal air sac method anti-angiogencsis model of Folkman et al, J. Exp Med 133 275 (1971), and the rat corneal micropocket ashay of Grmbrone, Jr. etal., J. Natl. Cancer Inst 52'413 (1974) in which corneal vascularization is induced in adult male rats of the Sprague-Dawley strain (Charles RiveT. Japan) by implanting 500 ng of bFGF (bovine, R&D Systems, Inc.), impregnated in ethylene-vmyl acetate copolymer pellets, m each cornea. In addition, a model exists m which angiogencsis is induced in NTH-Swiss or athymk nude (iw/nu) mice after implantation of MCF-7 breast carcinoma or NIII-OVCAR-3 ovanan carcinoma cells as described by Lindner and Borden, Int. J. Cancer 71 456 (1997) Additional tumor cell lines including (but not limited to) SK-MEL-1 human malignant melanoma cells may also be used to induce angiogeiiesis as described above. Vanous doses, with vanous dosing frequencies, and lor vanous duration can be tested for both the unmodified and PEGylated IFN-ß-la proteins of the invention Other methods for testing PEGylated murine and rat TFN-p for anb-angiogenic effects in an anirrul model include (but are not limited to) protocols for screening new potential unticancei agents as described in the onginal Cancer Chemotherapy Reports, Part 3, Vol 3, No 2, September 1972 and the supplement In Vivo Cancer Models, 1976-1982, NIH Publication No 84-2635, February 1984. Because of the species specificity of Type 1 interferons, to assess the ana-angiogemc activity of PEGylated IFN-P in rodent models, PEGylated rodent IFN-p preparations (e g., munne and rat) are generated. Such screening methods are exemplified by a protocol to test for the anti-angiogenic effects of PEGylated munne IFN-P on subcutaneously-implanted Lewis Lung Carcinoma: Origin ot Tumor Line This tumor line arose spontaneously in 1951 as a carcinoma uf the lung in a C57BL/6 mouse. Summary of Test Procedure A tumor fragment is implanted subcutaneously in the axillary region of a B6D2F1 mouse The test agent (i e., a PEGylated interferon of the invention) is administered at various doses, subcutaneously (SC) or intraperitoneally (IP) on multiple days following tumor implantation. The parameter measured is median survival time. Results are expressed as a percentage of control survival time. Animals Propagation- C57BL/6 mice Testing B6D2F1 mice Weight. Mice are within a 3 g weight range, with a minimum weight of 18 g for males and 17 g for females. Sex- One sex is used for all test and control animals in one experiment. Source1 One source, if feasible, for all animals in one experiment Experiment Size Ten animals per test group Tumor Transfer PROPAGATION- Fragment Prepare a 2-4 mm fragment of a SC donor tumor. Time Day 13-15 Site, Implant the fragment SC in the axillary region with a puncture in the inguinal region TESTING: Fragment: Prepare a 2-4 mm fragment of SC donor tumor Time. Day 13-15. Site Implant the fragment SC in the axillary region with a puncture m the inguinal region Testing Schedule Day 0 Implant rumor Run bacterial cultures Test positive control compound in every odd-numbered experiment Prepare materials. Record deaths daily. Day 1 • Check cultures Discard experiment if contaminated Randomize animals Treat as instructed (on day 1 and on following days) Day 2. Recheck cultures. Discard experiment if contaminated. Day i. Weigh Day 2 and day of initial test agent toxicity evaluation. Day 14: Control early-death day Day 48: Control no-lake day. Day 60: End and evaluate experiment Examine lungs for tumor Qualify Control Schedule the positive control compound (NSC 26271; Cytoxan at a dose of 100 mg/kg/injecnon) in every odd-numbered experiment, the regimen tor which is intraperitoneal on Day 1 only The lower Test/Control limit for the positive control is 140%. The acceptable untreated control median survival time is 19-35 6 days Evaluation The pnrametEr measuied is median survival time Compute the mean animal body weights for Day 1 and Day 5, compute Test/Control iatio for all test groups The mean animal body weights, fur staging day and final evaluation day are computed. The Test/Control ratio is computed for all test groups with >65% survivors on Day 5 A Test/Control ratio value Criteria for Activity An initial Test/Control ratio greater than or equal to 140% is considered necessaiy to demonstrate moderate actrvit> A reproducible Test/Control ratio value of greater than or equal to 150% is considered significant activity EXAMPLE 8 In vivo models to test the antiproliferativ e and anti-tumor effects of PEGyiated human IFN-O-la and PEGyiated rodent IFNs-p Various in vivo models are available to test the anti-prohterative and anti-tumor effects of unmodified and PEGyiated human JFNs-ß-la of the invention- In a model descnbed by Bailon ct al, Bioconjugate Chemistry 12.195 (2001), athymic nude mice (Harlan) are implanted subcutanconsly with 2 x 106 human renal A498, human renal ACHN, or human renal G402 cells under the rear flank and 3-6 weeks allowed for tumors to develop Unmodified or PEGyiated human IFN-ß-la is then administered at various doses, with various dosing frequencies, and for various duration, and tumor volume measured and compared between treatments In another model described by Lindner and Borden, J. Interferon Cytokine Res 17' 681 (1997), athymic nude (nulnu) oophorectonwed Iemdle BALB/c mice are implanted with 2 \ 10* MC*-"7 (plus estradiol), MDA-MB-231, MDA-MB-46S. or BT-20 human breast carcinoma cells, NEH-OVCAR-3 human ovarian carcinoma cells, HT-29 human colon carcinoma cells, or SK-MEL-] or FEMX human malignant mehnoma cells, into the dermis overlying the mammary glands nearest the axillae, and the size of the tumors assessed as a function of time Unmodified or PEGyiated human IFN-pM a is then administered at various doses, with various dosing frequencies, and for various duration, and tumor volume measured and compared between treatments Other models for testing the anti-proliferative and antitumor effects of PEGyiated human IFN-ß- la include (but are not limited to) local and metastatic lung cancer models described by Qin et al, Molecular Therapy 4 356 (2001), and nude mouse xenograft models of human colorectal cancel liver metastases described by Tada et al, J Clinical Investigation 108- 83 (2001) Other methods for testing PEGylated murine and raL IFN-ß for anb-prnlifenirive and anti-tumor effects in animal models include (but are not limited to) a mouse model of" malignant mesothelioma described by Odaka et al, Cancer Res 61. 6201 (2001), local and metastatic lung cancer models described by Qin et al, Molecular Therapy 4: 356 (2001), and syngeneic mouse models of colorectal cancer liver metastases described by Tada et al, J Clinical Investigation 108 83 (2001). EXAMPLE 9 In vivo models to test anti-viral effects of PEGylated murine IFN-P and PEGylated human IFN-ß-la An in vivo mouse model is available to test the effect of unmodified and PEGylated munne IFN-p on the levels of human Hepatitis B Virus (HBV) in HBV-transgcmc SCID mice Larkin et al, Nature Medicine 5'907 (1999). In this model, transgenic SCID mice carrying a head-to-tail drmer of the human HBV genome have detectable levels of HBV rephcative forms and pre-gcnomic RNA in the liver, and HBV virus m the berum. Hepatocytes from the transgenic mice are also positive for the HBsAg, HBcAg, and HbxAg proteins, indicative of viral replication An example of a protocol for comparing unmodified and PEGylated murine IFN-P in thib model is given below. 30 mice (5 groups of 5 plus 5 spare) with comparable viral titer arc titered at two independent time points (at least 1 week apart) to establish a baseline titer and to ensure that their titers remain constant prior to dosing with munne IFN-ß- Groups of 5 mice are dosed 3 times per week (Monday, Wednesday, and Friday) subcutaneously with the following samples, as shown in Table 7 Table 7 (Table Removed) Viral titers are determined weekly during dosing and weekly to br-weeldy for 6 months Mowing dosing Plots of viral tiler against time are constructed for a comparison of vehicle and IFN-ß-treated animals with respect to the clearance and re-establishment of viral titer. A second study is then performed with the appropriate doses of unmodified and PEGylated murine IFN-ß with 10-20 mice per group for a total of 30-60 mice (10-20 for control, 10-20 for unmodified murine IFN-p, and 10-20 for PEGylated murine IFN-p), Viral titers are assessed as above, and at sacrifice, serum is analyzed for viral titer as well as for HbsAg by SDS-PAGE and Western blotting Livers are also Temoved, frozen or fixed as necessary, and stained for the presence of HbsAg, HbcAg, and HbxAg. Other appropriate histological, histoehemical, or biochemical tests familiar to those in the art may also be performed on serum and tissue samples An in vivo mouse model is also available to test the el feet of unmodified and PEGylated human IFN-ß-la on the levels of human Hepatitis C Virus (HCV) in mice carrying chimaenc human livers, Mercer et al., Nature Medicine 7*927 (2001). In this model, normal human hepatocytes are grafted into SCID mice carrying a plasminogen acrivaxor transgene (Aib-uPA) and the mice inoculated with serum from humans infected with the different gentoypes of HCV. The engrafted human liver cells become mfected by the viras and the virus replicates. Levels of HCV RNA in the serum can be quantified by PCK, as well as the levels of positive and negative (rephcative form) RNA in the liver cells. An appropriate study protocol similar to (but not limited to) that described above for unmodified and PEGylated murine IFN-p in transgenic HBV SCID mice is performed to assess the efficacy of unmodified and PEGylated human IFN-ß-1 a in this model i.e. to determine the effect of treatment on HCV titer, liver histology, serum ALT levels, and the presence of HCV rephcative forms in the engrafted human liver tissue Other appropriate histological, histochemical, or biochemical tests familiar to those in (he art may also be performed on serum and tissue samples We Claim 1. A polyalkylene glycol polymer compound having the structure according to Formula I: (Formula Removed) wherein P is a polyalkylene glycol polymer; X is O, S, CO, CO2, COS, SO, SO2, CONR', SO2NR', or NR'; R' is hydrogen, a straight- or branched-chain, saturated or unsaturated C1 to C20 alkyl or heteroalkyl group, C3 to C8 saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or Linsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, ihioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido. amidine, imine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkylthio; Z and Z' are individually hydrogen, a straight- or branched-chain, saturated or unsaturated C1 to C20 alkyl or heteroalkyl group, C3 to Cg saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkylthio, provided that at least one Z or Z' is not hydrogen; R is -R*-B or a moiety suitable for forming a bond between the compound of Formula I and a biologically-active compound or precursor thereof; R* is a linking moiety; B is a biologically-active molecule; each n is independently 0 or an integer from 1 to 5; and p is 1, 2, or 3. 2. The compound as claimed in claim 1, wherein said compound has the structure of Formula X: (Formula Removed) wherein P is a polyalkylene glycol polymer; X is O, S, CO, CO2, COS, SO, SO2, CONR', SO2NR', or NR'; R' is hydrogen, a straight- or branched-chain, saturated or unsaturated C1 to C20 alkyl or heteroalkyl group, C3 to C8 saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkylthio; Z and Z' are individually hydrogen, a straight- or branched-chain, saturated or unsaturated C1 to C20 alkyl or heteroalkyl group, C3 to C8 saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkylthio, provided that at least one Z or Z' is not hydrogen; R is a moiety suitable for forming a bond between the compound of Formula X and a biologically-active compound or precursor thereof; each n is independently 0 or an integer from 1 to 5; and p is 1, 2. or 3. 3. The compound as claimed in claim 2, wherein R is chosen from the group consisting of carboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succinimidyl, isocyanate, isothiocyanate, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, hydroxysuccinimidyl, azole, maleimide, sulfone, allyl, vinylsulfone, tresyl, sulfo-N-succinimidyl, dione, mesyl, tosyl, and glyoxal. 4. The compound as claimed in claim 2, wherein P is a polyethylene glycol having the structure of Formula II: (Formula Removed) wherein E is hydrogen, a straight- or branched-chain C| to C20 alkyl group, or a detectable label; and a is an integer from 4 to 10,000. 5. The compound as claimed in claim 4, wherein E is methyl. 6. The compound as claimed in claim 2, wherein P is a polyethylene glycol having the structure of Formula II: (Formula Removed) wherein E is a moiety suitable for forming a bond between the compound of Formula X and a biologically-active compound or precursor thereof and a is an integer from 4 to 10,000. 7. The compound as claimed in claim 6, wherein E is chosen from the group consisting of carboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succinimidyl, isocyanate, isothiocyanate, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, hydroxysuccinimidyl, azole, maleimide, sulfone, allyl, vinylsulfone, tresyl, sulfo-N-succinimidyl, dione, mesyl, tosyl, and glyoxal. 8. The compound as claimed in claim 7, wherein E has the structure according to Formula III: (Formula Removed) wherein X and Y are independently O, S, CO, CO2, COS, SO, SO2, CONR', SO2NR', or NR'; Q is a C3 to Cg saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group, or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidine, imine. cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkylthio; R" and Z are independantly as described above; m is 0 or 1; each W is, independently, hydrogen or a Ci to C7 alkyl; each n is independently 0 or an integer from 1 to 5; and R" is a moiety suitable for forming a bond between the compound of Formula III and a biologically-active compound or precursor thereof. 9. The compound as claimed in claim 6, wherein E has the structure according to Formula IV: (Formula Removed) wherein each X, Z and n are, independently, as defined; each W is, independently, hydrogen or a C1 to C7 alkyl; and R'" is a moiety suitable for forming a bond between the compound of Formula IV and a biologically-active compound or precursor thereof. 10 The compound as claimed in claim 8, wherein R" is chosen from the group consisting of carboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succinimidyl, isocyanate, isothiocyanate, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, hydroxysuccinimidyl, azole, maleimide, sulfone, allyl, vinylsulfone, tresyl, sulfo-N-succinimidyl, dione, mesyl, tosyl, and glyoxal. 11. The compound as claimed in claim 9, wherein R'" is chosen from the group consisting of carboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succinimidyl, isocyanate, isothiocyanate, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, hydroxysuccinimidyl, azole, maleimide. sulfone, allyl, vinylsulfone, tresyl, sulfo-N-succinimidyl, dione, mesyl, tosyl, and glyoxal. 12. The compound as claimed in claim 4, wherein E is a detectable label. 13. The compound as claimed in claim 11, wherein E is selected from the group consisting of radioactive isotopes, fluorescent moieties, phosphorescent moieties, chemiluminescent moieties, and quantum dots. 14. The compound as claimed in claim 2, wherein said compound has the structure according to Formula Xa: (Formula Removed) is a polyalkylene glycol polymer; X is O, S, CO, CO2, COS, SO, SO2, CONR', SO2NR', or NR'; R' is hydrogen, a straight- or branched-chain, saturated or unsaturated C1 to C20 alkyl or heteroalkyl group, C3 to C8 saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkylthio; is a straight- or branched-chain, saturated or unsaturated C1 to C20 alkyl or heteroalkyl group, C3 to C8 saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted alkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkylthio; R is a moiety suitable for forming a bond between the compound of Formula Xa and a biologically-active compound or precursor thereof; and n is 0 or an integer from 1 to 5. 15. The compound as claimed in claim 14, wherein R is chosen from the group consisting of carboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succinimidyl, isocyanate, isothiocyanate, dithiopyridine. vinylpyridine, iodoacetamide, epoxide, hydroxysuccinimidyl, azole, maleimide, sulfone, allyl, vinylsulfone, tresyl, sulfo-N-succinimidyl, dione, mesyl, tosyl, and glyoxal. 16. The compound as claimed in claim 14, wherein P is a polyethylene glycol having the structure of Formula II: (Formula Removed) wherein E is hydrogen, a straight- or branched-chain C1 to C20 alkyl group, or a detectable label; and a is an integer from 4 to 10,000. 17. The compound as claimed in claim 16, wherein E is methyl. 1 8. The compound as claimed in claim 14, wherein P is a polyethylene glycol having the structure of Formula II: (Formula Removed) wherein E is a moiety suitable for forming a bond between the compound of Formula Xa and a biologically-active compound or precursor thereof and a is an integer from 4 to 10,000. 19. The compound as claimed in claim 18, wherein E is chosen from the group consisting of carboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succinimidyl, isocyanate, isothiocyanate, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, hydroxysuccinimidyl, azole, maleimide, sulfone, allyl, vinylsulfone, tresyl, sulfo-N-succinimidyl, dione, mesyl, tosyl, and glyoxal. 20. The compound as claimed in claim 18, wherein E has the structure according to Formula III: (Formula Removed) wherein X and Y are independently O, S, CO, CO2, COS, SO, SO2, CONR', SO2NR', or NR'; Q is a C3 to Cg saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group, or a substituted or unsubstituted alkaryl wherein the alkyl is a Q to C2o saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidine, imine, cyano. nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkylthio; R' and each Z are independently as described above; m is 0 or 1: each W is, independently, hydrogen or a C1 to C7 alkyl; each n is independently 0 or an integer from 1 to 5; and R" is a moiety suitable for forming a bond between the compound of Formula III and a biologically-active compound or precursor thereof. 21. The compound as claimed in claim 18, wherein E has the structure according to Formula IV: (Formula Removed) wherein X, Z and n are as defined; each W is, independently, hydrogen or a C1 to C7 alkyl; and R'" is a moiety suitable for forming a bond between the compound of Formula IV and a biologically-active compound or precursor thereof. 22. The compound according to claim 20, wherein R" is chosen from the group consisting of carboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succinimidyl, isocyanate, isothiocyanate, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, hydroxysuccinimidyl, azole, maleimide, sulfone, allyl, vinylsulfone, tresyl, sulfo-N-succinimidyl, dione, mesyl, tosyl, and glyoxal. 23. The compound as claimed in claim 21, wherein R'" is chosen from the group consisting of carboxylic acid, ester, aldehyde, aldehyde hydrate, acetal, hydroxy, protected hydroxy, carbonate, alkenyl, acrylate, methacrylate, acrylamide, substituted or unsubstituted thiol, halogen, substituted or unsubstituted amine, protected amine, hydrazide, protected hydrazide, succinimidyl, isocyanate, isothiocyanate, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, hydroxy succinimidyl, azole, maleimide, sulfone, allyl, vinylsulfone, tresyl, sulfo-N-succinimidyl, dione, mesyl, tosyl, and glyoxal. 24. The compound as claimed in claim 16, wherein E is a detectable label. 25 The compound as claimed in claim 23, wherein E is selected from the group consisting of radioactive isotopes, fluorescent moieties, phosphorescent moieties, chemiluminescent moieties, and quantum dots. 26. The compound as claimed in claim 14, having the structure of Formula XI: (Formula Removed) wherein P is a polyalkylene glycol polymer; and n and Z are as defined. 27. The compound as claimed in claim 26, wherein said compound has the structure of Formula XII: (Formula Removed) wherein n is 0 or an integer from 1 to 5; a is an integer from 4 to 10,000; and Z is a straight- or branched-chain, saturated or unsaturated C1 to C20 alkyl or heteroalkyl group, C3 to C8 saturated or unsaturated cyclic alkyl or cyclic heteroalkyl, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted ulkaryl wherein the alkyl is a C1 to C20 saturated or unsaturated alkyl or heteroalkaryl group, wherein the substituents are selected from the group consisting of halogen, hydroxyl, carbonyl, carboxylate, ester, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aromatic moiety, heteroaromatic moiety, imino, silyl, ether, and alkylthio. 28. The compound as claimed in claim 27, wherein Z is methyl. 29. The compound as claimed in claim 27, wherein n is one. 30. The compound as claimed in claim 27, having the structure of Formula XIII: (Formula Removed) wherein a is an integer from 4 to 10,000. 31. The compound as claimed in any one of claims 2-13, wherein Z and Z' are individually hydrogen or a straight- or branched-chain saturated C\ to C20 alkyl or heteroalkyl group, provided that at least one Z or Z* is not hydrogen. 32. The compound as claimed in any one of claims 2-25 or 31, wherein X is O. 33. The compound as claimed in any one of claims 14-27, wherein Z is a straight- or branched-chain saturated C1 to C20 alkyl group. 34. The compound as claimed in any one of claims 2-25, 31, or 32, wherein R is aldehyde. 35. Use of a compound of Formula I as a pharmaceutical composition. 36. The polyalkylene glycol polymer compound as herein described with reference to the foregoing examples and accompanying drawing. |
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| Patent Number | 270273 | ||||||||||||||||||||||||
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| Indian Patent Application Number | 2388/DELNP/2004 | ||||||||||||||||||||||||
| PG Journal Number | 50/2015 | ||||||||||||||||||||||||
| Publication Date | 11-Dec-2015 | ||||||||||||||||||||||||
| Grant Date | 08-Dec-2015 | ||||||||||||||||||||||||
| Date of Filing | 17-Aug-2004 | ||||||||||||||||||||||||
| Name of Patentee | BIOGEN, IDEC MA INC. | ||||||||||||||||||||||||
| Applicant Address | 14 CAMBRIDGE CENTER, CAMBRIDGE MA 02142, U.S.A. | ||||||||||||||||||||||||
Inventors:
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| PCT International Classification Number | A61K 47/48 | ||||||||||||||||||||||||
| PCT International Application Number | PCT/US03/01559 | ||||||||||||||||||||||||
| PCT International Filing date | 2003-01-17 | ||||||||||||||||||||||||
PCT Conventions:
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