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 any one of glycine, alanine, lysine, and arginine;
b. x is an integer from 3-6;
c. A is a chemical group or moiety comprising an alkyl group with 6 to 36 carbon units with a —OCH(CH 3 )CO— linker attached to -(Cm) x -peptide; and
d. the A-(Cm) x -peptide has lower biological activity in cell culture than the parent peptide in the absence of serum, wherein the peptide has at least 8 amino acids and is not SEQ ID NO: 53, or wherein the peptide is auristatin.
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 vasopressin, 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).
4. The composition of claim 2 , wherein the peptide is GLP-1 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 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).
12. The composition of claim 1 , wherein the peptide is GLP-1 and A-(Cm) x - is not attached to the N terminus of the peptide.
13. The composition of claim 1 , wherein A is a linear alkyl.
14. The composition of claim 11 , wherein A is a linear alkyl.
15. The composition of claim 12 , wherein A is a linear alkyl.
16. The composition of claim 1 , wherein A is a branched alkyl.
17. The composition of claim 12 , wherein A is a branched alkyl.
18. The composition of claim 12 , wherein A is a branched alkyl.
19. A method of making a composition comprising a peptide analog comprising:
forming a covalent bond between a parent peptide and a group A-(Cm) x - (reactive group) to form a composition comprising peptide analog according to claim 1 , where said peptide analog has lower biological activity in cell culture than the parent peptide in the absence of serum.
20. A method for treatment of diabetes in a subject comprising administering the composition of claim 4 or the composition of claim 12 to a patient in need thereof.