Potent and biased agonists of class B1 GPCRs from a heterochiral design strategy

Glucagon is used to treat severe hypoglycaemia in patients with diabetes, and PTH(1-34), an N-terminal fragment of parathyroid hormone, is used to treat osteoporosis. Each peptide activates a cognate G-protein-coupled receptor (GPCR). High-resolution structures of peptide-receptor complexes show that glucagon and PTH(1-34) are fully α-helical in the bound state. Here we describe a design strategy that destabilizes the helical conformation of glucagon or PTH(1-34) but nevertheless delivers potent agonists of each receptor. Replacement of multiple L-α-amino-acid residues with D-α-amino-acid residues, at selected positions, generates heterochiral analogues of both glucagon and PTH(1-34) that approach the all-L peptide in receptor activation potency (cAMP production). The heterochiral agonists are biased away from β-arrestin recruitment relative to the all-L peptide. The glucagon analogues are also biased away from receptor internalization relative to glucagon itself. These unanticipated findings for two dissimilar class B1 GPCRs raise the prospect that heterochiral design will be impactful for other members of this receptor family, which includes multiple therapeutic targets.