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

Triple activation of the glucagon-like peptide 1 receptor, the GIP receptor, and the glucagon receptor shows promising effects for obesity treatment.

• The newly designed xGLP-1-based triagonists exhibit potent activity at the GLP-1R and GCGR, with weaker activation of the GIPR.
• xGLP/GCG/GIP-32 demonstrates superior weight loss effects compared to tirzepatide while maintaining similar metabolic efficacy to retatrutide.
• Preliminary studies indicate that xGLP/GCG/GIP-32 may exhibit biased agonism toward the GIPR and GCGR.
• This suggests that focusing on potent activation of all three receptors may not be necessary for effective treatment.
• Optimal receptor activation ratios could be explored further for triple agonists with receptor-biased agonism.

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