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Updated: Nov 17, 2025

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
Development of Generic G Protein Peptidomimetics Able to Stabilize Active State Gs Protein-Coupled Receptors for
Morgane Mannes1, Charlotte Martin1, Sarah Triest2
1Research Group of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussels, Belgium.
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.
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