Discovery of Insulin/GLP-1/Glucagon Triagonists for the Treatment of Diabetes and Obesity.

ABSTRACT: The combination of insulin and incretin-based therapies has emerged as a potential promising tactic for the treatment of diabetes. Here we report the first example of a unimolecular triagonist to simultaneously target insulin, GLP-1, and glucagon receptors, aiming for better glycemic control and superior weight loss. The strategy for constructing such a unimolecular triagonist is the conjugation of the insulin moiety and GLP-1R/GCGR coagonist peptide via alkyne-azide click chemistry. Two tractable series differentiated by insulin conjugation sites, B1^F and B29^K, were identified. Triagonist 13 prepared through the conjugation at insulin B1^F and position 24 of GLP-1R/GCGR coagonist exhibited insulin activity comparable to that of insulin degludec and potent and balanced GLP-1R and GCGR activities. Pharmacokinetic profiles of 13 in both rat and minipig were also discussed.

SUBMITTER: Huang C 

PROVIDER: S-EPMC9377023 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature