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

Morgane Mannes, Charlotte Martin, Sarah Triest, Marilisa Pia Dimmito, Adriano Mollica, Toon Laeremans, Christel J. Menet, Steven Ballet

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 (β2AR) 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.

Original languageEnglish
Pages (from-to)10247-10254
Number of pages8
JournalAngewandte Chemie International Edition
Volume60
Issue number18
DOIs
Publication statusPublished - 26 Apr 2021

Keywords

  • allosteric modulators
  • drug discovery
  • fragment screening
  • GPCRs
  • peptidomimetics

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