Development of a potent Xenopus GLP-1-derived GLP-1/GIP/Y₂ receptor tri-agonist for obesity and type 2 diabetes.

The drug development strategy of combining the complementary effects of different endogenous metabolism related hormones into one molecule is receiving increasing attention. In this study, we developed the unimolecular GLP-1/GIP/Y receptor triple agonist, aiming to simultaneously activating the GLP-1 and GIP receptors together with the appetite-curbing Y receptor to achieve better weight loss and blood glucose control. One strategy for constructing this triple agonist peptide involves coupling the GLP-1/GIP receptor dual agonist moiety with the PYY moiety through a maleimide-thiol specific reaction. Another strategy is to directly synthesize peptides with essentially identical sequences through solid-phase synthesis. Through long-acting modifications and comprehensive receptor screening, we identified a novel triple agonist, GP-38, exhibiting potent and balanced activity at GIP, GLP-1, and Y receptor. In diet-induced obesity mice, GP-38 showed favourable effects on lipid metabolism, weight reduction, and glucose homeostasis with semaglutide and cagrisema used as control. Collectively, these data demonstrate that GP-38, a highly potent triple agonist targeting GLP-1, GIP, and Y receptor, significantly outperforms GLP-1 receptor monotherapy in improving glucose homeostasis and reducing body weight, offers a promising pathway for the development of new treatments for obesity and type 2 diabetes.