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 the Apoe knockout 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.