Eunice Murage - Development of Potent Glucagon-like Peptide-1 Agonists with High Enzyme Stability via Introduction of Multiple Lactam Bridges

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  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

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