Strategic Design of Triple GLP-1R/GCGR/GIPR Agonists with Varied Receptor Potency: Achieving Comparable Glycemic and Weight Reduction Effects.

J Med Chem · 2025

Last updated 2026-05-28

Researchers designed a new triple-acting drug (xGLP/GCG/GIP-32) that targets three receptors—GLP-1, GCG, and GIP—with strong effects on GLP-1 and GCG but weaker effects on GIP. In tests, this drug led to similar improvements in blood sugar control and weight loss as two existing drugs (tirzepatide and retatrutide), even though it had less potent GIP activity. The findings suggest that strong activation of all three receptors may not be necessary for effective results.

AI summary of the abstract below.

Journal	J Med Chem, 2025
Citations	5
Relative citation ratio	1.93
Molecules	—
Conditions studied	Type 2 Diabetes, Obesity

Abstract

Triple activation of the glucagon-like peptide 1 receptor (GLP-1R), the GIP receptor (GIPR), and the glucagon receptor (GCGR) is an innovative strategy for treating obesity and diabetes. We report the rational design of triple GLP-1R/GCGR/GIPR agonists, featuring potent GLP-1R and GCGR activity with weaker GIPR activation. Using sequence analysis, molecular dynamics simulations, docking, and amino acid optimization, we developed xGLP-1-based triagonists, with xGLP/GCG/GIP-32 exhibiting a unique activation profile. It shows superior weight loss effects compared to tirzepatide and similar metabolic efficacy to retatrutide, despite significantly less potent GIPR activity. Preliminary mechanistic studies revealed that xGLP/GCG/GIP-32 exhibits biased agonism toward the GIPR and GCGR. These activity data suggest it may not be imperative to focus solely on potent activation of all three receptors. Especially for triple agonists with receptor-biased agonism, there may be room to explore optimal receptor activation ratios.

Verbatim abstract via PubMed 40958513 ↗