Polymer conjugates of therapeutic peptides
View Patent ↗The invention provides peptides that are chemically modified by covalent attachment of a water-soluble oligomer. A conjugate of the invention, when administered by any of a number of administration routes, exhibits characteristics that are different from the characteristics of the peptide not attached to the water-soluble oligomer.
1. A conjugate having the structure:
where:
mPEG is CH 3 O—(CH 2 CH 2 O) n CH 2 CH 2 —;
n is an integer from 10 to 1800;
R 1 is H or lower alkyl;
R 2 is H or lower alkyl;
X 1 and X 2 are each independently —NH—C(O)—CH 2 —O—, —NH—C(O)—(CH 2 ) q —O—, —NH—C(O)—(CH 2 ) q —CO—NH—, —NH—C(O)—(CH 2 ) q —, or —C(O)—NH—;
q is 2, 3, 4, or 5;
˜NH-ZICO is an amino group of a ziconotide moiety; and
k is 1, 2, or 3.
2. The conjugate of claim 1 , wherein the ziconotide moiety is prepared by chemical synthesis.
3. The conjugate of claim 1 , wherein mPEG has a weight-average molecular weight in a range of from about 2,000 Daltons to about 50,000 Daltons.
4. The conjugate of claim 3 , wherein mPEG has a weight-average molecular weight in a range of from about 5,000 Daltons to about 40,000 Daltons.
5. The conjugate of claim 1 , wherein ˜NH-ZICO is at an amino-terminal amino acid of the ziconotide moiety.
6. The conjugate of claim 1 , wherein ˜NH-ZICO is at an epsilon amino group of an internal lysine amino acid of the ziconotide moiety.
7. The conjugate of claim 1 , prepared using a polymeric reagent selected from the following:
8. The conjugate according to claim 1 , wherein the ziconotide comprises the amino acid sequence of SEQ ID NO: 264.
9. A pharmaceutical composition comprising the conjugate of claim 1 and a pharmaceutically acceptable excipient.
10. A method of treatment comprising administering the conjugate of claim 1 to a subject in need thereof.
11. The conjugate of claim 1 , having a structure selected from:
12. The conjugate of claim 1 , wherein k is 1.