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Papers of the Week

Papers: 28 Nov 2020 - 4 Dec 2020

Animal Studies, Pharmacology/Drug Development

2020 Nov 27

Commun Biol



The PAR2 inhibitor I-287 selectively targets Gα and Gα signaling and has anti-inflammatory effects.


Avet C, Sturino C, Grastilleur S, Gouill C L, Semache M, Gross F, Gendron L, Bennani Y, Mancini JA, Sayegh CE, Bouvier M
Commun Biol. 2020 Nov 27; 3(1):719.
PMID: 33247181.


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 Gα and Gα activity and their downstream effectors, while having no effect on G 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.