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ACS Chem Biol. 2016 Feb 19;11(2):324-8. doi: 10.1021/acschembio.5b00787. Epub 2016 Jan 4.

Design of Potent and Proteolytically Stable Oxyntomodulin Analogs.

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California Institute for Biomedical Research (Calibr) , 11119 North Torrey Pines Road, La Jolla, California 92037, United States.
Department of Chemistry, State University of New York at Buffalo , Buffalo, New York 14260-3000, United States.
Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.


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.

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