Development of Generic G Protein Peptidomimetics Able to Stabilize Active State Gs Protein-Coupled Receptors for Application in Drug Discovery

Abstract

G protein-coupled receptors (GPCRs) represent an important group of membrane proteins that play a central role in modern medicine. Unfortunately, conformational promiscuity hampers full therapeutic exploitation of GPCRs, since the largest population of the receptor will adopt a basal conformation, which subsequently challenges screens for agonist drug discovery programs. Herein, we describe a set of peptidomimetics able to mimic the ability of G proteins in stabilizing the active state of the β₂ adrenergic receptor (β₂ AR) and the dopamine 1 receptor (D1R). During fragment-based screening efforts, these (un)constrained peptide analogues of the α₅ helix in G_s proteins, were able to identify agonism pre-imprinted fragments for the examined GPCRs, and as such, they behave as a generic tool, enabling an engagement in agonist earmarked discovery programs.

Keywords: GPCRs; allosteric modulators; drug discovery; fragment screening; peptidomimetics.