Thioester-terminated water soluble polymers and method of modifying the N-terminus of a polypeptide therewith
View Patent ↗The invention provides reagents and methods for conjugating a polymer specifically to the α-amine of a polypeptide. The invention provides monofunctional, bifunctional, and multifunctional PEGs and related polymers having a terminal thioester moiety capable of specifically conjugating to the α-amine of a polypeptide having a cysteine or histidine residue at the N-terminus. The invention provides reactive thioester-terminated PEG polymers that have suitable reactivity with an N-terminal cysteine or histidine residue of a polypeptide to produce an amide bond between the PEG molecule and the polypeptide.
1. A composition comprising a conjugate having the structure:
wherein:
R′ is a central core molecule;
POLY is a water-soluble and non-peptidic polymer backbone;
Z is a linker;
a is 0 or 1;
m is from 0 to about 12;
each X is independently selected from H and alkyl;
Y is a heteroatom;
W is CH 2 SH or
POLYPEPTIDE is a residue of a polypeptide molecule; and
y is from 3 to about 100.
2. The composition of claim 1 , wherein the central core molecule, R′, is a residue of a polyol having at least three hydroxyl groups.
3. The composition of claim 2 , wherein the polyol is selected from the group consisting of glycerol, hexaglycerol, sorbitol and pentaerythritol.
4. The composition of claim 3 , wherein the polyol is pentaerythritol.
5. The composition of claim 1 , wherein the water-soluble and non-peptidic polymer backbone, POLY, is a poly(ethylene glycol).
6. The composition of claim 1 , wherein the poly(ethylene glycol) has a molecular weight of about 100 Da to about 100,000 Da.
7. The composition of claim 1 , wherein the linker, Z, is selected from the group consisting of —O—, —S—, —NHCO—, —CONH—, —O 2 C—, —NH—CO 2 — and —O 2 CNH—.
8. The composition of claim 1 , wherein the linker, Z, is —NHCO—.
9. The composition of claim 1 , wherein m is 1 to about 4.
10. The composition of claim 8 , wherein m is 2.
11. The composition of claim 1 , wherein the hetereoatom, Y, is O or S.
12. The composition of claim 11 , wherein the heteroatom, Y, is O.
13. The composition of claim 1 , wherein W is CH 2 SH.
14. The composition of claim 1 , wherein W is
15. The composition of claim 1 , wherein y is 3 to about 25.
16. The composition of claim 15 , wherein y is 3-10.
17. The composition of claim 16 , wherein y is 4.