Chimeric fibroblast growth factor (FGF) 2/FGF1 peptides and methods of use
The present disclosure provides chimeric proteins having an N-terminus coupled to a C-terminus, wherein the N-terminus comprises an N-terminal portion of fibroblast growth factor (FGF) 2 and the C-terminus comprises a portion of an FGF1 protein, wherein the chimeric protein comprises at least 95% sequence identity to SEQ ID NO: 9, 10, 11, 12 or 13. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. Methods of using the disclosed molecules to reduce blood glucose levels are also provided.
1. A method of reducing blood glucose in a mammal, comprising:
administering a therapeutically effective amount of a chimeric protein to the mammal, thereby reducing the blood glucose, wherein the chimeric protein comprises an N-terminus coupled to a C-terminus, wherein the N-terminus comprises an N-terminal portion of an fibroblast growth factor (FGF) 2 protein and the C-terminus comprises a portion of an FGF1 protein, wherein the chimeric protein comprises at least 95% sequence identity to SEQ ID NO: 9.
2. The method of claim 1 , wherein the therapeutically effective amount of the chimeric protein is at least 0.5 mg/kg.
3. The method of claim 1 , wherein the administering is subcutaneous, intraperitoneal, intramuscular, or intravenous.
4. The method of claim 1 , wherein the mammal is a cat or dog.
5. The method of claim 1 , wherein the mammal is a human.
6. The method of claim 1 , wherein the chimeric protein is administered in combination with an additional therapeutic compound.
7. The method of claim 6 , wherein the additional therapeutic compound is an alpha-glucosidase inhibitor, amylin agonist, dipeptidyl-peptidase 4 (DPP-4) inhibitor, meglitinide, sulfonylurea, or a peroxisome proliferator-activated receptor (PPAR)-gamma agonist.
8. The method of claim 7 , wherein the PPAR-gamma agonist is a thiazolidinedione (TZD), aleglitazar, farglitazar, muraglitazar, or tesaglitazar.
9. The method of claim 8 , wherein the TZD is pioglitazone, rosiglitazone, rivoglitazone, or troglitazone.
10. The method of claim 1 , wherein the chimeric protein comprises at least 96% sequence identity to SEQ ID NO: 9.
11. The method of claim 1 , wherein the chimeric protein comprises at least 97% sequence identity to SEQ ID NO: 9.
12. The method of claim 1 , wherein the chimeric protein comprises at least 98% sequence identity to SEQ ID NO: 9.
13. The method of claim 1 , wherein the chimeric protein comprises at least 99% sequence identity to SEQ ID NO: 9.
14. The method of claim 1 , wherein the chimeric protein comprises SEQ ID NO: 9.
15. The method of claim 1 , wherein the chimeric protein consists of SEQ ID NO: 9.
16. The method of claim 1 , wherein the chimeric protein comprises 1 to 8 conservative amino acid substitutions.
17. A method of reducing fed and fasting blood glucose, improving insulin sensitivity and glucose tolerance, reducing systemic chronic inflammation, ameliorating hepatic steatosis in a mammal, or combinations thereof, comprising:
administering a therapeutically effective amount of a chimeric protein to the mammal, thereby reducing fed and fasting blood glucose, improving insulin sensitivity and glucose tolerance, reducing systemic chronic inflammation, ameliorating hepatic steatosis in a mammal, or combinations thereof, wherein the chimeric protein comprises an N-terminus coupled to a C-terminus, wherein the N-terminus comprises an N-terminal portion of an fibroblast growth factor (FGF) 2 protein and the C-terminus comprises a portion of an FGF1 protein, wherein the chimeric protein comprises at least 95% sequence identity to SEQ ID NO: 9.
18. The method of claim 17 , wherein the therapeutically effective amount of the chimeric protein is at least 0.5 mg/kg.
19. The method of claim 17 , wherein the administering is subcutaneous, intraperitoneal, intramuscular, or intravenous.
20. The method of claim 17 , wherein the mammal is a cat or dog.
21. The method of claim 17 , wherein the mammal is a human.
22. The method of claim 17 , wherein the chimeric protein is administered in combination with an additional therapeutic compound.
23. The method of claim 17 , wherein the additional therapeutic compound is an alpha-glucosidase inhibitor, amylin agonist, dipeptidyl-peptidase 4 (DPP-4) inhibitor, meglitinide, sulfonylurea, or a peroxisome proliferator-activated receptor (PPAR)-gamma agonist.
24. The method of claim 23 , wherein the PPAR-gamma agonist is a thiazolidinedione (TZD), aleglitazar, farglitazar, muraglitazar, or tesaglitazar.
25. The method of claim 24 , wherein the TZD is pioglitazone, rosiglitazone, rivoglitazone, or troglitazone.
26. The method of claim 17 , wherein the chimeric protein comprises at least 96% sequence identity to SEQ ID NO: 9.
27. The method of claim 17 , wherein the chimeric protein comprises at least 97% sequence identity to SEQ ID NO: 9.
28. The method of claim 17 , wherein the chimeric protein comprises at least 98% sequence identity to SEQ ID NO: 9.
29. The method of claim 17 , wherein the chimeric protein comprises at least 99% sequence identity to SEQ ID NO: 9.
30. The method of claim 17 , wherein the chimeric protein comprises SEQ ID NO: 9.
31. The method of claim 17 , wherein the chimeric protein consists of SEQ ID NO: 9.
32. The method of claim 17 , wherein the chimeric protein comprises 1 to 8 conservative amino acid substitutions.