Composition for long-acting peptide analogs
View Patent ↗The invention describes compositions of peptide analogs that are active in blood or cleavable in blood to release an active peptide. The peptide analogs have a general formula: A-(Cm) x -Peptide (SEQ ID NO: 76), wherein A is hydrophobic moiety or a metal binding moiety, e.g., a chemical group or moiety containing 1) an alkyl group having 6 to 36 carbon units, 2) a nitrilotriacetic acid group, 3) an imidodiacetic acid group, or 4) a moiety of formula (Z y His w ) p (SEQ ID NO: 50), wherein Z is any amino acid residue other than histidine, His is histidine, y is an integer from 0-6; w is an integer from 1-6; and p is an integer from 1-6; wherein if A has alkyl group with 6 to 36 carbon units x is greater than 0; and Cm is a cleavable moiety consisting of glycine or alanine or lysine or arginine or N-Arginine or N-lysine, wherein x is an integer between 0-6 and N may be any amino acid or none. The peptide analogs are complexed with polymeric carrier to provide enhanced half-life.
1. A composition comprising a peptide analog having a general formula: A-(Cm)x-(peptide), wherein:
a. Cm is each independently lysine or arginine;
b. x is an integer from 3-6;
c. A is an alkyl group with 6 to 36 carbon units with a linker group selected from carbonyl and amino; and
d. the peptide is selected from vasopressin or a derivative thereof, terlipressin or a derivative thereof, glucagon like peptide (GLP), leptin fragment, gastric inhibitory polypeptide (GIP), epidermal growth factor (EGF) receptor ligand, EGF, transforming growth factor alpha (TGF-alpha), gastrin/cholecystokinin receptor ligand, gastrin, cholecystokinin, auristatin, nisin, insulin, insulin-like growth factor, parathyroid hormone (PTH), atrial natriuretic factor, somatostatin, gonadotropin releasing hormone, leutinizing-hormone-releasing-hormone, and vasoactive intestinal peptide (VIP).
2. The composition of claim 1 , further comprising a polymeric carrier with a plurality of hydrophobic groups of 8-36 carbons each, wherein group A of the peptide analog is non-covalently bound to the plurality of hydrophobic groups of the polymeric carrier by hydrophobic interaction.
3. The composition of claim 2 , wherein the peptide is selected from the group consisting of terlipressin and derivatives thereof and atrial natriuretic factor, and A-(Cm)x- is attached to the N terminus of the peptide.
4. The composition of claim 2 , wherein the peptide is vasoactive intestinal peptide (VIP) or atrial natriuretic factor and A-(Cm)x- is attached to the C terminus of the peptide or a side chain.
5. The composition of claim 2 , wherein A is a linear alkyl.
6. The composition of claim 3 , wherein A is a linear alkyl.
7. The composition of claim 4 , wherein A is a linear alkyl.
8. The composition of claim 2 , wherein A is a branched alkyl.
9. The composition of claim 3 , wherein A is a branched alkyl.
10. The composition of claim 4 , wherein A is a branched alkyl.
11. The composition of claim 1 , wherein the peptide is selected from the group consisting of terlipressin and derivatives thereof and atrial natriuretic factor, and A-(Cm)x is attached to the N terminus of the peptide.
12. The composition of claim 1 , wherein A is a linear alkyl.
13. The composition of claim 11 , wherein A is a linear alkyl.
14. The composition of claim 1 , wherein A is a branched alkyl.
15. The composition of claim 11 , wherein A is a branched alkyl.
16. A method of making a peptide analog composition of claim 1 , comprising:
step (i): forming a covalent bond between a resin and a reactive group on a first amino acid to provide a resin comprising a covalently bonded amino acid;
step (ii): forming a covalent bond between the resin comprising the covalently bonded amino acid and a reactive group on a second amino acid;
step (iii): repeating step (ii) to provide a (Cm)x-peptide; and
forming a carbonyl or amino bond between the (Cm)x-peptide and an alkyl group with 6 to 36 carbon units to provide a peptide analog according to claim 1 .
17. A method for treatment of hypovolemia, ascites, splanchnic vasodilation, systemic vasodilation, hypotension, esophageal variceal hemorrhage, hepatorenal syndrome, or sepsis in a subject in need of such treatment comprising administering to the subject a pharmaceutical composition comprising a composition of claim 1 in pharmaceutically acceptable carrier wherein the peptide comprises sequence ID 53.
18. The composition of claim 1 , wherein the A-(Cm)x-(peptide) has lower biological activity in cell culture than the parent peptide in the absence of serum.
19. A composition comprising a peptide analog having a general formula: A-(Cm)x-(peptide), wherein:
a. Cm is each independently lysine, glycine, or arginine;
b. x is an integer from 2-6;
c. A is an alkyl group with 6 to 36 carbon units with a linker group selected from carbonyl and amino; and
d. the peptide comprises atrial natriuretic factor.
20. The composition of claim 19 , wherein the peptide is atrial natriuretic factor.
21. The composition of claim 19 , wherein x is 3 or 4.
22. The composition of claim 19 , wherein Cm is each independently lysine or glycine.
23. The composition of claim 19 , further comprising a polymeric carrier with a plurality of hydrophobic groups of 8-36 carbons each, wherein group A of the peptide analog is non-covalently bound to the plurality of hydrophobic groups of the polymeric carrier by hydrophobic interaction.
24. The composition of claim 1 , wherein the peptide is vasopressin or a derivative thereof.
25. The composition of claim 24 , wherein the peptide is vasopressin.
26. The composition of claim 24 , further comprising a polymeric carrier with a plurality of hydrophobic groups of 8-36 carbons each, wherein group A of the peptide analog is non-covalently bound to the plurality of hydrophobic groups of the polymeric carrier by hydrophobic interaction.
27. The composition of claim 1 , wherein the peptide is terlipressin or a derivative thereof.
28. The composition of claim 27 , wherein the peptide is terlipressin.
29. The composition of claim 27 , further comprising a polymeric carrier with a plurality of hydrophobic groups of 8-36 carbons each, wherein group A of the peptide analog is non-covalently bound to the plurality of hydrophobic groups of the polymeric carrier by hydrophobic interaction.
30. The composition of claim 1 , wherein the peptide is glucagon like peptide (GLP).
31. The composition of claim 30 , further comprising a polymeric carrier with a plurality of hydrophobic groups of 8-36 carbons each, wherein group A of the peptide analog is non-covalently bound to the plurality of hydrophobic groups of the polymeric carrier by hydrophobic interaction.
32. The composition of claim 1 , wherein the peptide is atrial natriuretic factor.
33. The composition of claim 32 , further comprising a polymeric carrier with a plurality of hydrophobic groups of 8-36 carbons each, wherein group A of the peptide analog is non-covalently bound to the plurality of hydrophobic groups of the polymeric carrier by hydrophobic interaction.
34. The composition of claim 1 , wherein the peptide is vasoactive intestinal peptide (VIP).
35. The composition of claim 34 , further comprising a polymeric carrier with a plurality of hydrophobic groups of 8-36 carbons each, wherein group A of the peptide analog is non-covalently bound to the plurality of hydrophobic groups of the polymeric carrier by hydrophobic interaction.
36. The composition of claim 1 , wherein the peptide is epidermal growth factor (EGF) receptor ligand.
37. The composition of claim 36 , further comprising a polymeric carrier with a plurality of hydrophobic groups of 8-36 carbons each, wherein group A of the peptide analog is non-covalently bound to the plurality of hydrophobic groups of the polymeric carrier by hydrophobic interaction.