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Development of Generic G Protein Peptidomimetics Able to Stabilize Active State G s Protein‐Coupled Receptors for Application in Drug Discovery
Author(s) -
Mannes Morgane,
Martin Charlotte,
Triest Sarah,
Pia Dimmito Marilisa,
Mollica Adriano,
Laeremans Toon,
Menet Christel J.,
Ballet Steven
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202100180
Subject(s) - g protein coupled receptor , peptidomimetic , drug discovery , receptor , agonist , g protein , computational biology , biology , chemistry , pharmacology , bioinformatics , biochemistry , peptide
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.