GLP-1 exendin-4 peptide analogs and uses thereof
The invention relates to novel polypeptide analogues of GLP-1 and exendin-4. The polypeptide, in a preferred embodiment, is insulinotropic and long-acting. Preferably, the polypeptide's insulinotropic effect is comparable to or exceeds the effect of an equimolar amount of GLP-1 or exendin-4. The invention also relates to a method of treating a subject with diabetes, comprising administering to the subject the polypeptide of the invention in an amount that has an insulinotropic effect. The invention also relates to methods of using GLP-1, exendin-4, and polypeptide analogues thereof for neuroprotective and neurotrophic effects.
1. A method of treating a subject with a neurodegenerative disease or of reducing one or more symptoms of a neurodegenerative disease in a subject in need thereof, wherein the neurodegenerative disease is peripheral neuropathy, comprising administering to the subject a therapeutically effective amount of a polypeptide comprising GLP-1, exendin-4, or a therapeutically effective GLP-1 or exendin-4 analogue, wherein the polypeptide binds to and activates a receptor that binds GLP-1, exendin-4, or both.
2. The method of claim 1 , wherein the polypeptide is insulinotropic.
3. The method of claim 1 , wherein the polypeptide is longer acting than GLP-1.
4. The method of claim 1 , wherein the polypeptide has a greater binding affinity for the GLP-1 receptor than does GLP-1.
5. The method of claim 1 , wherein the polypeptide is selected from the group consisting of SEQ ID NOs:9, 42-48, and 50-52.
6. The method of claim 1 , wherein the polypeptide comprises GLP-1 or a therapeutically effective GLP-1 analogue.
7. The method of claim 6 , wherein the polypeptide is selected from the group consisting of SEQ ID NOs:5-6 and 8.
8. The method of claim 6 , wherein the polypeptide is insulinotropic.
9. The method of claim 6 , wherein the polypeptide is longer acting than GLP-1.
10. The method of claim 6 , wherein the polypeptide has a greater binding affinity for the GLP-1 receptor than does GLP-1.
11. The method of claim 1 , wherein the polypeptide comprises exendin-4 or a therapeutically effective exendin-4 analogue.
12. The method of claim 11 , wherein the polypeptide is selected from the group consisting of SEQ ID NOs:10-12 and 33.
13. The method of claim 11 , wherein the polypeptide is insulinotropic.
14. The method of claim 11 , wherein the polypeptide is longer acting than GLP-1.
15. The method of claim 11 , wherein the polypeptide has a greater binding affinity for the GLP-1 receptor than does GLP-1.