The PAR2 inhibitor I-287 selectively targets G\u03b1q and G\u03b112/13 signaling and has anti-inflammatory effects

Charlotte Avet,Camil E Sayegh,Christian Le Gouill,Michel Bouvier,Florence Gross,Sébastien Grastilleur,Claudio Sturino,Youssef Bennani,Louis Gendron,Joseph A Mancini,Meriem Semache

doi:10.1038/s42003-020-01453-8

Abstract

Protease-activated receptor-2 (PAR2) is involved in inflammatory responses and pain, therefore representing a promising therapeutic target for the treatment of immune-mediated inflammatory diseases. However, as for other GPCRs, PAR2 can activate multiple signaling pathways and those involved in inflammatory responses remain poorly defined. Here, we describe a new selective and potent PAR2 inhibitor (I-287) that shows functional selectivity by acting as a negative allosteric regulator on Gαq and Gα12/13 activity and their downstream effectors, while having no effect on Gi/o signaling and βarrestin2 engagement. Such selective inhibition of only a subset of the pathways engaged by PAR2 was found to be sufficient to block inflammation in vivo. In addition to unraveling the PAR2 signaling pathways involved in the pro-inflammatory response, our study opens the path toward the development of new functionally selective drugs with reduced liabilities that could arise from blocking all the signaling activities controlled by the receptor.

Highlights

Protease-activated receptor-2 (PAR2) is involved in inflammatory responses and pain, representing a promising therapeutic target for the treatment of immune-mediated inflammatory diseases
As only a few numbers of studies have clearly demonstrated the direct coupling of PAR2 to specific Gα isoforms[23,24,25], we first established the profile of Gα subunits activated by human PAR2 using a BRET2based assay platform in human embryonic kidney 293 (HEK293) cells
PAR2 has been implicated in the pathogenesis of several immune-mediated inflammatory diseases (IMIDs) and cancers[2,37,38], only a limited number of compounds able to block its action are currently available

Summary

Introduction

Protease-activated receptor-2 (PAR2) is involved in inflammatory responses and pain, representing a promising therapeutic target for the treatment of immune-mediated inflammatory diseases. We describe a new selective and potent PAR2 inhibitor (I-287) that shows functional selectivity by acting as a negative allosteric regulator on Gαq and Gα12/13 activity and their downstream effectors, while having no effect on Gi/o signaling and βarrestin[2] engagement. Such selective inhibition of only a subset of the pathways engaged by PAR2 was found to be sufficient to block inflammation in vivo. In addition to unraveling the PAR2 signaling pathways involved in the pro-inflammatory response, our study opens the path toward the development of new functionally selective drugs with reduced liabilities that could arise from blocking all the signaling activities controlled by the receptor. PAR2 activation results in the release of inflammatory cytokine and chemokine from keratinocytes, endothelial, and epithelial cells[13]

Methods

Results

Conclusion