AI-Guided De Novo Design Pipeline for Oral, Gut-Active Peptides That Stimulate GLP-1 Secretion and Promote Weight Loss in Diet-Induced Obese Rats

Abstract Glucagon-like peptide-1 (GLP-1) receptor agonists have transformed obesity treatment, yet gastrointestinal intolerance, high cost and weight regain after discontinuation highlight the need for complementary strategies. Stimulating endogenous GLP-1 via nutrient-sensing G protein-coupled receptors on enteroendocrine L cells offers a route to modulate satiety pathways. We developed a peptide design platform that couples AlphaFold2-based structural and AI-guided modeling with de novo and pharmacophore-guided design for nutrient-sensing GPCRs, integrated with high-throughput peptide synthesis and in vitro screening. Iterative refinement over four rounds yielded peptides producing >27-fold increases in GLP-1 secretion in STC-1 cells, exceeding the effect of an optimized small-molecule GLP-1 secretagogue in vitro. In diet-induced obese rats, 28 days of oral dosing reduced food intake and body weight with semaglutide as an active comparator. Our work establishes a framework for nutritional ingredient discovery and a blueprint for functional peptides targeting gut hormone systems associated with metabolic health.