Thioester-terminated water soluble polymers and method of modifying the N-terminus of a polypeptide therewith

1. A formulation comprising a polymer conjugate of a polypeptide having a cysteine or histidine residue at the N-terminus, said polymer conjugate comprising a water soluble and non-peptidic polymer backbone having at least one terminus bonded to the structure:

wherein:

L is the point of bonding to the polymer backbone;

Z is a linker;

Y is a heteroatom;

m is from 0 to about 12;

each X is independently selected from H and alkyl;

a is 0 or 1;

W is —CH 2 SH or

POLYPEPTIDE is a residue of the polypeptide molecule.

2. The formulation of claim 1 , wherein the polymer backbone is poly(ethylene glycol).

3. The formulation of claim 1 , wherein POLYPEPTIDE is a residue of a polypeptide selected from the group consisting of proteins, protein-ligands, enzymes, cytokines, hematopoietins, growth factors, hormones, antigens, antibodies, antibody fragments, receptors, and protein fragments.

4. The formulation of claim 1 , wherein POLYPEPTIDE is a residue of an interferon molecule.

5. The formulation of claim 1 , wherein each X is H or C1-C6 alkyl.

6. The formulation of claim 5 , wherein each X is H or methyl.

7. The formulation of claim 1 , wherein Y is O or S.

8. The formulation of claim 1 , wherein a is 1 and Z is selected from the group consisting of —O—, —S—, —NHCO—, —CONH—, —O 2 C—, —NHCO 2 —, and —O 2 CNH—.

9. The formulation of claim 1 , wherein the polymer backbone is selected from the group consisting of poly(alkylene glycol), poly(oxyethylated potyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline, poly(N-acryloylmorpholinc), polyacrylate, polyacrylamides, polysaccharides, and copolymers, terpolymers, and mixtures thereof.

10. The formulation of claim 1 , wherein the polymer backbone is selected from the group consisting of poly(ethylene glycol, poly(propylene glycol), and copolymers of ethylene glycol and propylene glycol.

11. The formulation of claim 1 , wherein the polymer backbone is poly(ethylene glycol) having a number average molecular weight of about 100 Da to about 100,000 Da.

12. The formulation of claim 11 , wherein the poly(ethylene glycol) has a number average molecular weight of about 2,000 Da to about 60,000 Da.

13. The formulation of claim 11 , wherein the poly(ethylene glycol) has the formula —CH 2 CH 2 O—(CH 2 CH 2 O)n-CH 2 CH 2 —, wherein n is from about 1 to about 2000.

14. The formulation of claim 1 , wherein m is 1 to about 4.

15. The formulation of claim 1 , having the structure:

wherein:

R is methoxy;

POLY is poly(ethylene glycol) having a number average molecular weight of about 2,000 Da to about 60,000 Da;

each X is H or CH 3 ;

m is 1 to about 4;

W is —CH 2 SH or

POLYPEPTIDE is a residue of the polypeptide molecule.

16. The formulation of claim 15 , wherein X is H and m is 1.

17. The formulation of claim 15 , wherein each X is H and m is 2.

18. The formulation of claim 15 , wherein —(CH(X)) m — has the structure —CH 2 —CH 2 —CH(CH 3 )—.

19. A formulation comprising a polymer conjugate of a polypeptide having a cysteine molecule at the N-terminus, said polymer conjugate comprising two water soluble and non-peptidic polymer backbones attached at the N-terminus, the conjugate having the structure:

wherein:

L is the point of bonding to each of said two polymer backbones;

L′ and Z are linkers;

Y is a heteroatom;

m is from 0 to about 12;

each X is independently selected from H and alkyl;

a is 0 or 1; and

POLYPEPTIDE is a residue of the polypeptide molecule.

20. The formulation of claim 19 , wherein L′ is selected from the group consisting of