Exploring the signaling space of a GPCR using bivalent ligands with a rigid oligoproline backbone

G protein-coupled receptors (GPCRs) are one of the most important drug-target classes in pharmaceutical industry. Their diversity in signaling, which can be modulated with drugs, permits the design of more effective and better-tolerated therapeutics. In this work, we have used rigid oligoproline backbones to generate bivalent ligands for the gastrin-releasing peptide receptor (GRPR) with a fixed distance between their recognition motifs. This allows the stabilization of GPCR dimers irrespective of their physiological occurrence and relevance, thus expanding the space for medicinal chemistry. Specifically, we observed that compounds presenting agonists or antagonists at 20- and 30-A distance induce GRPR dimerization. Furthermore, we found that 1) compounds with two agonists at 20- and 30-angstrom distance that induce dimer formation show bias toward Gq efficacy, 2) dimers with 20- and 30-angstrom distance have different potencies toward beta-arrestin-1 and beta-arrestin-2, and 3) the divalent agonistic ligand with 10-angstrom distance specifically reduces Gq potency without affecting beta-arrestin recruitment, pointing toward an allosteric effect. In summary, we show that rigid oligoproline backbones represent a tool to develop ligands with biased GPCR signaling.

Automated summary

This study demonstrates that using rigid oligoproline backbones can develop ligands with biased GPCR signaling, and stabilizing GPCR dimers by fixing the distance between their recognition motifs can expand the space for medicinal chemistry.