A Potent α/β-Peptide Analogue of GLP‑1 with Prolonged Action in

ABSTRACT: Glucagon-like peptide-1 (GLP-1) is a natural agonist for GLP-1R, a G protein-coupled receptor (GPCR) on the surface of pancreatic β cells. GLP-1R agoinsts are attractive for treatment of type 2 diabetes, but GLP-1 itself is rapidly degraded by peptidases in vivo. We describe a design strategy for retaining GLP-1-like activity while engendering prolonged activity in vivo, based on strategic replacement of native α residues with conforma-tionally constrained β-amino acid residues. This backbone-modification approach may be useful for developing stabilized analogues of other peptide hormones. Many vital physiological processes are modulated by Gprotein-coupled receptors (GPCRs) in the B family;1 their natural agonists are long polypeptide hormones (≥27 residues). Extensive efforts to develop small-molecule agonists or antagonists of these GPCRs have yielded little success, bu