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 |
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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 |
format | Article |
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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
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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
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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
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title | Development of Generic G Protein Peptidomimetics Able to Stabilize Active State G s Protein-Coupled Receptors for Application in Drug Discovery |
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