Co-agonists of the glucagon and GLP-1 receptors
View Patent ↗Described are peptide analogs of glucagon, which have been modified to be resistant to cleavage and inactivation by dipeptidyl peptidase IV (DPP-IV) and to increase in vivo half-life of the peptide analog while enabling the peptide analog to have relatively balanced agonist activity at the glucagon-like peptide 1 (GLP-1) receptor and the glucagon (GCG) receptor, and the use of such GLP-1 receptor/GCG receptor co-agonists for treatment of metabolic disorders such as diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and obesity.
1. A peptide, wherein the peptide has the amino acid sequence of SEQ ID NO: 7, 8, 10, 13, or 17, or a pharmaceutically acceptable salt thereof.
2. The peptide of claim 1 , wherein the pharmaceutically acceptable salt is the sodium salt.
3. A composition comprising the peptide of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
4. The composition of claim 3 , wherein the composition further comprises an insulin or insulin analog.
5. The composition of claim 4 , wherein the insulin analog comprises insulin detemir, insulin glargine, insulin levemir, insulin glulisine, or insulin lispro.
6. A peptide, wherein the peptide has the amino acid sequence of SEQ ID NO: 7, or a pharmaceutically acceptable salt thereof.
7. A peptide, wherein the peptide has the amino acid sequence of SEQ ID NO: 8, or a pharmaceutically acceptable salt thereof.
8. A peptide, wherein the peptide has the amino acid sequence of SEQ ID NO: 10, or a pharmaceutically acceptable salt thereof.
9. A peptide, wherein the peptide has the amino acid sequence of SEQ ID NO: 13, or a pharmaceutically acceptable salt thereof.
10. A peptide, wherein the peptide has the amino acid sequence of SEQ ID NO: 17, or a pharmaceutically acceptable salt thereof.
11. A peptide comprising the structure
HsQGTFTSDK(γEγEC 16 )SKYLDARAAQDFVQWLLDT-NH 2 (SEQ ID NO:10)
wherein “s” is D-serine, the lysine at position 10 is conjugated via its epsilon amino group to a C 16 fatty acid via a gamma-glutamic acid-gamma-glutamic acid dipeptide (γEγE) spacer, and the peptide, or a pharmaceutically acceptable salt thereof, has a C-terminal amine.
12. The peptide of claim 11 , wherein the pharmaceutically acceptable salt is the sodium salt.
13. A composition comprising the peptide of claim 11 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14. The composition of claim 13 , wherein the composition further comprises an insulin or insulin analog.
15. The composition of claim 14 , wherein the insulin analog comprises insulin detemir, insulin glargine, insulin levemir, insulin glulisine, or insulin lispro.
16. A composition comprising a peptide, or a pharmaceutically acceptable salt thereof, having an amino acid sequence as set forth in SEQ ID NO: 7, 8, 10, 13, or 17, and a pharmaceutically acceptable carrier.
17. The composition of claim 16 , wherein the composition further comprises an insulin or insulin analog.
18. The composition of claim 17 , wherein the insulin analog comprises insulin detemir, insulin glargine, insulin levemir, insulin glulisine, or insulin lispro.
19. The peptide of claim 16 , wherein the pharmaceutically acceptable salt is the sodium salt.
20. A method for treating a patient or individual for a metabolic disease comprising administering to the patient or individual an effective amount of the composition of claim 16 to treat the metabolic disease in the patient or individual, wherein the metabolic disease comprises diabetes, or obesity.
21. The method of claim 20 , wherein the diabetes comprises Type I diabetes, Type II diabetes, or gestational diabetes.
22. A method for treating a metabolic disease in a patient or individual comprising:
administering to the patient or individual (i) an effective amount of a composition comprising a peptide, or a pharmaceutically acceptable salt thereof, having an amino acid sequence as set forth in SEQ ID NO: 7, 8, 10, 13, or 17, and a pharmaceutically acceptable carrier, and administering to the patient or individual an effective amount of a composition comprising an insulin or insulin analog and a pharmaceutically acceptable carrier or (ii) an effective amount of a composition comprising a peptide, or a pharmaceutically acceptable salt thereof, having an amino acid sequence as set forth in SEQ ID NO: 7, 8, 10, 13, or 17, an insulin or insulin analog, and a pharmaceutically acceptable carrier,
wherein the composition treats the metabolic disease, wherein the metabolic disease comprises diabetes, or obesity.
23. The method of claim 22 , wherein the method in step (i) comprises
(a) administering the composition comprising the peptide at a time prior to administering the composition comprising the insulin or insulin analog;
(b) administering the composition comprising the insulin or insulin analog at a time prior to administering the composition comprising the peptide; or
(c) administering the composition comprising the peptide and the composition comprising the insulin or insulin analog at the same time.
24. The method of claim 22 , wherein the insulin analog comprises insulin detemir, insulin glargine, insulin levemir, insulin glulisine, or insulin lispro.
25. The method of claim 22 , wherein the diabetes comprises Type I diabetes, Type II diabetes, or gestational diabetes.
26. The method of claim 22 , wherein the pharmaceutically acceptable salt is the sodium salt.
27. A method for treating a patient or individual for having a metabolic disease, comprising administering to the patient or individual an effective amount of the peptide of claim 1 , or a pharmaceutically acceptable salt thereof, to treat the metabolic disease in the patient or individual, wherein the metabolic disease comprises diabetes, or obesity.
28. The method of claim 27 , wherein the diabetes comprises Type I diabetes, Type II diabetes, or gestational diabetes.
29. The method of claim 27 , wherein the metabolic disease is diabetes.
30. The method of claim 27 , wherein the metabolic disease is obesity.