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Updated: Oct 19, 2025

Screening Peptides that Activate MRGPRX2 using Engineered HEK Cells
Published on: November 6, 2021
Design, synthesis, and biological evaluation of novel pyrrolidinone small-molecule Formyl peptide receptor 2 agonists
Monika Maciuszek1, Almudena Ortega-Gomez2, Sanne L Maas2
1LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, UK; The William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK.
Abstract:
A series of Formyl peptide receptor 2 small molecule agonists with a pyrrolidinone scaffold, derived from a combination of pharmacophore modelling and docking studies, were designed and synthesized. The GLASS (GPCR-Ligand Association) database was screened using a pharmacophore model. The most promising novel ligand structures were chosen and then tested in cellular assays (calcium mobilization and β-arrestin assays). Amongst the selected ligands, two pyrrolidinone compounds (7 and 8) turned out to be the most active. Moreover compound 7 was able to reduce the number of adherent neutrophils in a human neutrophil static adhesion assay which indicates its anti-inflammatory and proresolving properties. Further exploration and optimization of new ligands showed that heterocyclic rings, e.g. pyrazole directly connected to the pyrrolidinone scaffold, provide good stability and a boost in the agonistic activity. The compounds of most interest (7 and 30) were tested in an ERK phosphorylation assay, demonstrating selectivity towards FPR2 over FPR1. Compound 7 was examined in an in vivo mouse pharmacokinetic study. Compound 7 may be a valuable in vivo tool and help improve understanding of the role of the FPR2 receptor in the resolution of inflammation process.
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