Branched water-soluble polymers and their conjugates
View Patent ↗The present invention provides branched water-soluble polymers that allow two or more water-soluble polymers to be conjugated to another species. The branched polymers provide access to therapeutic agents that are conjugated at a single site to two or more water-soluble polymers. The branched polymers are based upon branch points that are simple branched alkyl structures, reactive side-chain amino acids and small peptides of reactive side-chain amino acids, and saccharides. Also provided is a method for preparing mono-disperse poly(ethylene glycol) of a well-defined and determinable molecular weight, and a method for the rational end-functionalization of poly(ethylene glycol). Conjugates of the branched water-soluble polymers with diverse species, e.g., peptides, lipids, glycolipids and small molecules are also provided.
1. An amino acid having the formula:
wherein
A is a member selected from O, NH, and S;
R 11 , R 11′ , R 12 are independently selected from H, substituted or unsubstituted alkyl and water-soluble polymers, with the proviso that at least two of R 11 , R 11′ , R 12 are water-soluble polymer moieties; and
R 14 is a nucleotide sugar or comprises a saccharide moiety conjugated to a member selected from a peptide and a lipid; and
s is an integer selected from between 1 and 5.
2. The amino acid according to claim 1 , wherein said water-soluble polymer moieties comprise poly(ethylene glycol).
3. The amino acid according to claim 1 , having the formula:
4. The amino acid according to claim 3 , having the formula:
wherein
m is an integer selected from between 1 and 10,000; and
n is an integer selected from between 1 and 10.
5. The amino acid according to claim 1 , wherein R 14 is a nucleotide sugar.
6. The amino acid according to claim 1 , wherein R 14 comprises a saccharide moiety conjugated to a member selected from a peptide and a lipid.
7. The amino acid according to claim 1 , wherein said saccharide moiety is conjugated to a member selected from an amino acid and a glycosyl residue of a peptide.
8. The amino acid according to claim 7 , wherein said saccharide moiety is a glycosyl linking group between an amino acid and a peptide.
9. The amino acid according to claim 8 , wherein said saccharide moiety is an intact glycosyl linking group between an amino acid and a peptide.
10. A pharmaceutical formulation comprising the amino acid according to claim 1 and a pharmaceutically acceptable carrier.
11. The amino acid according to claim 2 , wherein said poly(ethylene glycol) moieties have a molecular weight selected from 5 Kd, 10 Kd, 20 Kd, and 30 Kd.
12. The amino acid according to claim 2 , wherein said poly(ethylene glycol) moieties have a molecular weight of 20 Kd.
13. The amino acid according to claim 1 , having the formula:
wherein n is an integer selected from 1 to 20,000.
14. The amino acid according to claim 1 , having the formula:
wherein
R 15 is H, a nucleotide phosphate, or a bond to an amino acid of a peptide or to a glycosyl moiety that is directly bound to an amino acid of a peptide, or indirectly bound to an amino acid of a peptide by its conjugation to a glycosyl residue attached to the amino acid;
L is a linker; and
n is an integer selected from 1 to 20,000.
15. The amino acid according to claim 14 , wherein L comprises an —NH—moiety.
16. A pharmaceutical formulation comprising the amino acid according to claim 5 and a pharmaceutically acceptable carrier.
17. A pharmaceutical formulation comprising the amino acid according to claim 6 and a pharmaceutically acceptable carrier.
18. A pharmaceutical formulation comprising the amino acid according to claim 13 and a pharmaceutically acceptable carrier.
19. A pharmaceutical formulation comprising the amino acid according to claim 14 and a pharmaceutically acceptable carrier.
20. A pharmaceutical formulation comprising the amino acid according to claim 15 and a pharmaceutically acceptable carrier.