Computational Peptide Design Cotargeting Glucagon and Glucagon-like Peptide-1 Receptors

[Image: see text] Peptides are sustainable alternatives to conventional therapeutics for G protein-coupled receptor (GPCR) linked disorders, promising biocompatible and tailorable next-generation therapeutics for metabolic disorders including type-2 diabetes, as agonists of the glucagon receptor (GCGR) and the glucagon-like peptide-1 receptor (GLP-1R). However, single agonist peptides activating GLP-1R to stimulate insulin secretion also suppress obesity-linked glucagon release. Hence, bioactive peptides cotargeting GCGR and GLP-1R may remediate the blood glucose and fatty acid metabolism imbalance, tackling both diabetes and obesity to supersede current monoagonist therapy. Here, we design and model optimized peptide sequences starting from peptide sequences derived from earlier phage-displayed library screening, identifying those with predicted molecular binding profiles for dual agonism of GCGR and GLP-1R. We derive design rules from extensive molecular dynamics simulations based on peptide–receptor binding. Our newly designed coagonist peptide exhibits improved predicted coupled binding affinity for GCGR and GLP-1R relative to endogenous ligands and could in the future be tested experimentally, which may provide superior glycemic and weight loss control.