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 imidiodacetic 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 independently selected from
(i) Gly,
(ii) Ala,
(iii) Arg,
(iv) Lys,
(v) (N)q-Lys, wherein N is any amino acid, q is 0 or 1, and
(vi) (N)q-Arg, wherein N is any amino acid, q is 0 or 1;
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 comprises 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, luteinizing-hormone-releasing-hormone, or 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 atrial natriuretic factor, and A-(Cm)x- is attached to the N-terminus of the peptide.
4. The composition in claim 2 , wherein the peptide is glucagon-like peptide (GLP) or atrial natriuretic factor.
5. 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 N-terminus or the C-terminus of the peptide or a side chain.
6. The composition of claim 2 , wherein A is a linear alkyl.
7. The composition of claim 3 , wherein A is a linear alkyl.
8. The composition of claim 4 , wherein A is a linear alkyl.
9. The composition of claim 5 , wherein A is a linear alkyl.
10. The composition of claim 2 , wherein A is a branched alkyl.
11. The composition of claim 3 , wherein A is a branched alkyl.
12. The composition of claim 4 , wherein A is a branched alkyl.
13. The composition of claim 5 , wherein A is a branched alkyl.
14. The composition of claim 4 , wherein the peptide is atrial natriuretic factor.
15. The composition of claim 1 , wherein Cm is each independently selected from Ala, Arg, and Lys.
16. The composition of claim 1 , wherein Cm is each independently selected from
(i) Gly,
(ii) (N)q-Lys, wherein N is any amino acid, q is 0 or 1, and
(iii) (N)q-Arg, wherein N is any amino acid, q is 0 or 1.
17. The composition of claim 1 , wherein the A-(Cm)x-(peptide) has lower biological activity in cell culture than a corresponding peptide lacking the A-(Cm)x in the absence of serum.
18. A composition comprising a peptide analog having a general formula: A-(Cm)x-peptide, wherein:
a. Cm is independently selected from
(i) Gly,
(ii) Ala,
(iii) Arg,
(iv) Lys,
(v) (N)q-Lys, wherein N is any amino acid, q is 0 or 1, and
(vi) (N)q-Arg, wherein N is any amino acid, q is 0 or 1;
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, amino, and —OCH(CH 3 )CO—;
wherein Cm has at least one Gly or one Ala linked directly to the peptide,
wherein the A-(Cm)x-(peptide) has lower biological activity in cell culture than a corresponding peptide lacking the A-(Cm)x in the absence of serum, and
wherein the peptide comprises 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, luteinizing-hormone releasing-hormone, or vasoactive intestinal peptide (VIP).
19. A method of making a peptide analog having a general formula: A-(Cm)x-peptide, wherein:
a. Cm is independently selected from
(i) Gly,
(ii) Ala,
(iii) Arg,
(iv) Lys,
(v) (N)q-Lys, wherein N is any amino acid, q is 0 or 1, and
(vi) (N)q-Arg, wherein N is any amino acid, q is 0 or 1;
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 comprises 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, luteinizing-hormone releasing-hormone, or vasoactive intestinal peptide (VIP), the method 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 the peptide analog.
20. The composition of claim 1 , wherein the peptide is an epidermal growth factor (EGF) receptor ligand.
21. The composition of claim 2 , wherein the peptide is an epidermal growth factor (EGF) receptor ligand.
22. The composition of claim 18 , wherein the peptide is an epidermal growth factor (EGF) receptor ligand.
23. The composition of claim 18 , 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.