Discovery of Biased Dual-Agonists of Glucagon-Like Peptide 1 and Glucagon Receptors through Mutation of a Conserved Aspartate

High Resolution Image Download MS PowerPoint Slide Peptide agonists of the glucagon-like peptide 1 receptor (GLP-1R) have demonstrated clinical efficacy for the management of type 2 diabetes and promote weight loss in addition to glucose-dependent insulin secretion. Monomolecular dual- or triagonists that engage GLP-1R, the glucagon receptor (GCGR), and/or the glucose-dependent insulinotropic polypeptide receptor (GIPR) extract additive metabolic and weight loss benefits over targeting the GLP-1R alone for the broad treatment of cardiometabolic disorders. Full agonism of these GPCRs through both G-protein and β-arrestin signaling arms may be suboptimal, promoting undesirable “off-target” effects and receptor desensitization. We have identified that mutations at Asp9 of glucagon (GCG) and GLP-1, as well as a GCGR/GLP-1R dual agonist, confer robust preference for cAMP production over β-arrestin recruitment in vitro . We demonstrate that a biased coagonist bearing a subtle Asp9Glu mutation promotes robust weight-loss in vivo, guiding the design of future agonists targeting these GPCRs for maximum benefits.