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

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 β 2 adrenergic receptor (β 2 AR) and the dopamine 1 receptor (D1R). During fragment‐based screening efforts, these (un)constrained peptide analogues of the α 5 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.