Finding molecules that selectively activate both blood sugar and energy control receptors by changing a key protein part

Mutations at Asp9 of glucagon and GLP-1 confer robust preference for cAMP production over beta-arrestin recruitment.

• Peptide agonists of the glucagon-like peptide 1 receptor (GLP-1R) are effective for managing type 2 diabetes and promoting weight loss.
• Monomolecular dual- or triagonists engaging GLP-1R, glucagon receptor (GCGR), and glucose-dependent insulinotropic polypeptide receptor (GIPR) may provide greater metabolic and weight loss benefits.
• Full agonism of these receptors through both G-protein and beta-arrestin signaling pathways may lead to undesirable effects and receptor desensitization.
• A biased coagonist with an Asp9Glu mutation has been shown to promote robust weight loss in vivo.
• Findings may guide the design of future agonists targeting these receptors for optimal therapeutic effects.

Simplified