Publication Details (including relevant citation information):
Eunice Murage, Guangzu Gao, Alessandro Bisello, Jung-Mo Ahn
J. Med. Chem. 2010, 53 17, 6412-6420.
Glucagon-like peptide-1 (GLP-1) has the ability to lower the blood glucose level, and its regulatory functions make it an attractive therapeutic agent for the treatment of type 2 diabetes. However, its rapid degradation by enzymes like dipeptidyl peptidase-IV DPP-IV) and neutral endopeptidase (NEP) 24.11 severely compromises its effective clinical use. Whereas specific DPP-IV inhibitors have been developed, NEP24.11 targets multiple sites in theGLP-1 sequence, which makes it difficult to block. To address this drawback, we have designed and synthesized conformationally constrained GLP-1 analogues by introducing multiple lactam bridges that stabilized both R-helices in the N- and C-terminal regions simultaneously. In addition to improving the receptor activation capability (up to 5-fold) by fixing the alpha-helical conformations required for optimal receptor interaction, the introduced lactam bridges provided outstanding shielding over NEP24.11 (half-life of>96 h). These highly constrained peptides are the first examples of NEP 24.11-resistant GLP-1 analogues