Development of Generic G Protein Peptidomimetics Able to Stabilize Active State Gs Protein‐Coupled Receptors for Application in Drug Discovery. (23rd March 2021)

• Record Type: Journal Article
• Authors: Mannes, Morgane; Martin, Charlotte; Triest, Sarah; Pia Dimmito, Marilisa; Mollica, Adriano; Laeremans, Toon; Menet, Christel J.; Ballet, Steven
• Is Part Of: Angewandte Chemie. Volume 133:Number 18(2021)
• Page Start: 10335
• Page End: 10342
• Publication Date: 2021-03-23
• Subjects: allosteric modulators -- drug discovery -- fragment screening -- GPCRs -- peptidomimetics; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.202100180
• Languages: English
• ISSNs: 0044-8249

Abstract

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 Gs 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. Abstract : Based on the crystal structure of the β2 AR coupled to the Gs protein, a helical key epitope was chosen as a template to design peptidomimetics able to stabilize active‐state Gs protein‐coupled receptors. Radioligand assays were performed in the presence of the peptide mimetics and demonstrated the stabilization of Gs receptors in active conformation, opening a gateway for fragment‐based, agonist‐earmarked drug discovery programs.