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, w...

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Veröffentlicht in:Angewandte Chemie International Edition 2021-04, Vol.60 (18), p.10247-10254
Hauptverfasser: Mannes, Morgane, Martin, Charlotte, Triest, Sarah, Pia Dimmito, Marilisa, Mollica, Adriano, Laeremans, Toon, Menet, Christel J, Ballet, Steven
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container_end_page 10254
container_issue 18
container_start_page 10247
container_title Angewandte Chemie International Edition
container_volume 60
creator Mannes, Morgane
Martin, Charlotte
Triest, Sarah
Pia Dimmito, Marilisa
Mollica, Adriano
Laeremans, Toon
Menet, Christel J
Ballet, Steven
description 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 adrenergic receptor (β AR) and the dopamine 1 receptor (D1R). During fragment-based screening efforts, these (un)constrained peptide analogues of the α helix in G 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.
doi_str_mv 10.1002/anie.202100180
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