Stapled, Long-Acting Xenopus GLP-1-Based Dual GLP-1/Glucagon Receptor Agonists with Potent Therapeutic Efficacy for Metabolic Disease

• DOI: 10.1021/acs.molpharmaceut.0c00995
• Publication Date: 2021-07-09T14:13:06Z
• Authors: Chun Han; Yuqing Sun; Qimeng Yang; Feng Zhou; Xinyu Chen; Lintao Wu; Lidan Sun; Jing Han
• Keywords: Glucagon receptor

Novel peptidic glucagon receptor (GCGR) and glucagon-like peptide 1 (GLP-1R) dual agonists are reported to have increased efficacy over GLP-1R monoagonists for the treatment of diabetes obesity. We identified a novel Xenopus GLP-1-based GLP-1R/GCGR agonist (xGLP/GCG-13) designed with proper activity ratio favoring versus GCGR. However, clinical utility xGLP/GCG-13 is limited by its short in vivo half-life. Starting from xGLP/GCG-13, Cys mutation was performed, followed covalent side-chain stapling serum albumin binder incorporation, resulting stabilized secondary structure, enhanced potency at GCGR, improved stability. The lead 2c (stapled analogue palmitic acid binder) exhibits balanced GCGR activations potent, long-lasting effects on glucose control. further explored pharmacologically diet-induced obesity db/db rodent models. Chronic administration potently induced body weight loss hypoglycemic effects, tolerance, energy expenditure, normalized lipid metabolism adiposity relevant animal These results indicated that has potential development as antidiabetic and/or antiobesity drug. Furthermore, we propose incorporation protein-binding motif into di-Cys staple an effective method improving stabilities bioactivities peptides. This approach likely applicable other therapeutic peptides, such glucose-dependent insulin-tropic (GIPR) or GLP-1R/GCGR/GIPR triagonists.