Design of Potent and Proteolytically Stable Oxyntomodulin Analogs

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• 作者：Avinash Muppidi ; Huafei Zou ; Peng Yu Yang ; Elizabeth Chao ; Lance Sherwood ; Vanessa Nunez ; Ashley K. Woods ; Peter G. Schultz ; Qing Lin ; Weijun Shen
• 刊名：ACS Chemical Biology
• 出版年：2016
• 出版时间：February 19, 2016
• 年：2016
• 卷：11
• 期：2
• 页码：324-328
• 全文大小：313K
• ISSN：1554-8937

文摘

Incretin-based peptides are effective therapeutics for treating type 2 diabetes mellitus (T2DM). Oxyntomodulin (OXM), a dual agonist of GLP-1R and GCGR, has shown superior weight loss and glucose lowering effects, compared to single GLP-1R agonists. To overcome the short half-life and rapid renal clearance of OXM, which limit its therapeutic potential, both lipid and PEG modified OXM analogs have been reported. However, these approaches often result in reduced potency or PEG-associated toxicity. Herein, we report a new class of cross-linked OXM analogs that show increased plasma stability and higher potency in activating both GLP-1R and GCGR. Moreover, the extended in vivo half-life results in superior antihyperglycemic activity in mice compared to the wild-type OXM.