Glucagon/GLP-1 receptor co-agonists

Patent metadata

Field	Value
Publication number	US-9309301-B2
Application number	US-201214127469-A
Country	US
Kind code	B2
Filing date	Jun 12, 2012
Priority date	Jun 22, 2011
Publication date	Apr 12, 2016
Grant date	Apr 12, 2016

Abstract

Provided herein are peptides and variant peptides that exhibit enhanced activity at the GLP-1 receptor, as compared to native glucagon.

First claim

The invention claimed is:

1. A peptide comprising
or a pharmaceutically acceptable salt thereof.

2. A variant peptide comprising the amino acid sequence of the peptide of claim 1 but differs in one or more of the following ways:
a. the variant peptide comprises an acylated amino acid or an alkylated amino acid;
b. an acylated amino acid or an alkylated amino acid is replaced with the corresponding amino acid of native glucagon (SEQ ID NO: 1) at that position or a conservative substitution of the native amino acid, and optionally a new acylated or alkylated amino acid is introduced at a different position;
c. the variant peptide comprises an amino acid covalently attached to a hydrophilic moiety;
d. an amino acid covalently attached to a hydrophilic moiety is replaced with the corresponding amino acid of native glucagon (SEQ ID NO: 1) at that position, and optionally a new amino acid covalently attached to a hydrophilic moiety is introduced at a different position;
e. the C-terminal amino acid of the variant peptide comprises a C-terminal amide in place of a C-terminal alpha carboxylate;
f. an amino acid at any of positions 1 through 29 is replaced with the corresponding amino acid of native glucagon (SEQ ID NO: 1) at that position;
g. or any combinations thereof;

or a pharmaceutically acceptable salt thereof.

3. The variant peptide of claim 2 , comprising (i) a hydrophilic moiety covalently attached to an amino acid at position 16, 17, 21, 24, 29, a position within a C-terminal extension, or at the C-terminus, (ii) a hydrophilic moiety covalently attached to an amino acid selected from the group consisting of: Cys, Lys, Orn, homocysteine, and Ac-Phe, (iii) or a combination thereof.

4. The variant peptide of claim 3 , wherein the hydrophilic moiety is a polyethylene glycol.

5. The variant peptide of claim 3 , wherein the hydrophilic moiety is a polyethylene glycol having a molecular weight of 40 kda.

6. The variant peptide of any of claim 2 , comprising (i) an acylated or alkylated amino acid at position 10; (ii) an acylated or alkylated amino acid which an acylated or alkylated amino acid of Formula I, Formula II, or Formula III, optionally, wherein the amino acid of Formula I is Lys, or (iii) an acylated or alkylated amino acid, wherein the acyl group or alkyl group is covalently attached to the amino acid via a spacer, optionally, wherein the spacer is an amino acid or a dipeptide.

7. The variant peptide of claim 6 , comprising an acylated or alkylated amino acid which comprises a C8 to C20 alkyl chain, a C12 to C18 alkyl chain, or a C14 or C16 alkyl chain.

8. The variant peptide of claim 6 , wherein the spacer comprises one or two acidic residues.

9. The variant peptide of claim 2 , wherein the (EC50 at the glucagon receptor)/(EC50 at the GLP-1 receptor) is about 20 or less.

10. The peptide variant of claim 2 , wherein the (EC50) at the glucagon receptor)/(EC50 at the GLP-1 receptor) is about 20 or less.

11. A conjugate comprising a variant peptide of claim 2 conjugated to a heterologous moiety.

12. The conjugate of claim 11 , wherein the heterologous moiety comprises one or more of: a peptide, a polypeptide, a nucleic acid molecule, an antibody or fragment thereof, a polymer, a quantum dot, a small molecule, a toxin, a diagnostic agent.

13. The conjugate of claim 11 , comprising an extension of 1-21 amino acids C-terminal to the amino acid at position 29 or the variant peptide.

14. The conjugate of claim 13 , wherein the extension is selected from the group consisting of: Gly, Glu, Cys, Gly-Gly, Gly-Glu, GPSSGAPPPS (SEQ ID NO: 9) or GGPSSGAPPPS (SEQ ID NO: 10).

15. A dimer or multimer comprising a variant peptide of claim 2 .

16. A pharmaceutical composition comprising the variant peptide of claim 2 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. A method of treating a disease or medical condition in a patient in need of treatment, wherein the disease or medical condition is selected from the group consisting of: metabolic syndrome, diabetes, obesity and liver steatosis, comprising administering to the patient the pharmaceutical composition of claim 16 in an amount effective to treat the disease or medical condition.

18. A conjugate comprising the peptide of claim 1 conjugated to a heterologous moiety.

19. The conjugate of claim 18 , wherein the heterologous moiety comprises one or more of: a peptide, a polypeptide, a nucleic acid molecule, an antibody or fragment therefore, a polymer, a quantum dot, a small molecule, a toxin, or a diagnostic agent.

20. The conjugate of claim 19 , comprising an extension of 1-21 amino acids C-terminal to the amino acid at position 29 of the peptide.

21. The conjugate of claim 20 , wherein the extension is selected from the group consisting of: Gly, Glu, Cys, Gly-Gly, Gly-Glu, GPSSGAPPPS (SEQ ID NO: 9) or GGPSSGAPPPS (SEQ ID NO: 10).

22. A dimer or multimer comprising the peptide of claim 1 .

23. A pharmaceutical composition comprising the peptide of claim 1 , or a pharmaceutically acceptable salt; and a pharmaceutically acceptable carrier.

24. A method of treating a disease or medical condition in a patient in need of treatment, wherein the disease or medical condition is selected from the group consisting of: metabolic syndrome, diabetes, obesity and liver steatosis, comprising administering to the patient the pharmaceutical composition of claim 23 in an amount effective to treat the disease or medical condition.

Assignees

• Dimarchi Richard D
• Smiley David L
• Yang Bin S
• Univ Indiana Res & Tech Corp

Inventors

• Dimarchi Richard D
• Smiley David L
• Yang Bin S

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title