Long-Acting and Stapled GLP-1R/GIPR/GCGR Triple Agonist for the Treatment of Obesity and Atherosclerosis.

Unimolecular multireceptor coagonists have emerged as a promising approach in the development of next-generation GLP-1 therapeutics. Herein, we describe the development of a long-acting and stapled GLP-1R/GIPR/GCGR triple agonist that exhibits balanced bioactivities comparable with those of their native ligands along with improved pharmacokinetic parameters. A robust and straightforward solid-phase Ugi macrocyclization strategy enables the facile synthesis of targeted peptides with a side-chain protractor attached on the exocyclic lactam bridge. In obese mice, the lead candidate UTG-4 demonstrates enhanced efficacy in promoting weight loss, suppressing food intake, and improving glucose tolerance and liver health compared to the clinically approved GLP-1R monoagonist semaglutide and GLP-1R/GIPR dual agonist tirzepatide. UTG-4 also exhibits remarkable antiatherosclerotic effects in theknockout mice. Studies using human aortic endothelial cells reveal that UTG-4 effectively alleviates the endothelial-to-mesenchymal transition, a key process implicated in atherosclerosis progression. These results highlight the therapeutic potential of UTG-4 for combating metabolic disorders and reducing cardiovascular risks.