Stabilized insulinotropic peptides and methods of use
The present invention provides stably crosslinked insulinotropic polypeptides having superior and unexpected benefits in the treatment of conditions involving abnormal glucose homeostasis, e.g., type 2 diabetes and conditions relating to type 2 diabetes. Such benefits include, but are not limited to, extended polypeptide half-life, enhanced alpha-helicity, improved thermal stability and protease resistance, increased functional activity and pharmacologic properties, improved bioavailability when administered by any route, and improved bioavailability and gastrointestinal absorption when delivered orally, as compared to the corresponding unmodified polypeptides. The invention also provides compositions for administering the polypeptides of the invention, as well as methods for preparing and evaluating the polypeptides of the invention.
1. A method for treating diabetes comprising administering a therapeutically effective amount of a cross-linked polypeptide comprising an alpha helix and one or more hydrocarbon staples, wherein each hydrocarbon staple covalently couples two non-natural amino acids within the alpha helix of said polypeptide, and wherein the cross-linked polypeptide comprises exenatide, gastric inhibitory polypeptide preprotein (GIPP), gastric inhibitory peptide (GIP), glucagon-like peptide-1 precursor (GLP-1P), glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), GLP-1 (7-37), GLP-1-(7-36), liraglutide, taspoglutide, albiglutide or LY2189265.
2. The method of claim 1 , wherein the cross-linked polypeptide is exenatide.
3. The method of claim 1 , wherein the cross-linked polypeptide is administered via an oral delivery route.
4. The method of claim 1 , wherein the cross-linked polypeptide is administered via an injection-based route.
5. The method of claim 1 , wherein the cross-linked polypeptide is administered via an oral delivery route and wherein the level of bioavailable polypeptide delivered orally is about equivalent to the level of bioavailable polypeptide delivered intravenously.