The PAR2 inhibitor I-287 selectively targets Gαq and Gα12/13 signaling and has anti-inflammatory effects
| Autor: | Charlotte Avet, Louis Gendron, Camil Elie Sayegh, Joseph A. Mancini, Florence Gross, Christian Le Gouill, Meriem Semache, Youssef L. Bennani, Claudio Sturino, Michel Bouvier, Sébastien Grastilleur |
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| Rok vydání: | 2020 |
| Předmět: |
Bioluminescence Resonance Energy Transfer Techniques
Male 0301 basic medicine Cell biology medicine.drug_class Allosteric regulation Anti-Inflammatory Agents Medicine (miscellaneous) Inflammation GTP-Binding Protein alpha Subunits G12-G13 Article General Biochemistry Genetics and Molecular Biology Anti-inflammatory Mice 03 medical and health sciences 0302 clinical medicine Cell Line Tumor medicine Functional selectivity Animals Humans Receptor PAR-2 Receptor beta-Arrestins G protein-coupled receptor Drug discovery Chemistry Effector Interleukin-8 Mice Inbred C57BL 030104 developmental biology 030220 oncology & carcinogenesis GTP-Binding Protein alpha Subunits Gq-G11 medicine.symptom Signal transduction General Agricultural and Biological Sciences Signal Transduction |
| Zdroj: | Communications Biology |
| ISSN: | 2399-3642 |
| Popis: | 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. Avet et al. characterize I-287, an inhibitor to protease-activated receptor 2 using BRET-assays. They find that I-287 selectively inhibits Gαq and Gα12/13 without affecting the activation of Gi/o or the recruitment of βarrestin2 and that it blocks inflammation in vitro and in vivo. |
| Databáze: | OpenAIRE |
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