变构调节
信号转导
调节器
炎症
G蛋白偶联受体
受体
功能选择性
细胞生物学
效应器
体内
化学
药理学
生物
免疫学
生物化学
基因
生物技术
作者
Charlotte Avet,Claudio F. Sturino,Sébastien Grastilleur,Christian Le Gouill,Meriem Semache,Florence Gross,Louis Gendron,Youssef L. Bennani,Joseph A. Mancini,Camil E. Sayegh,Michel Bouvier
标识
DOI:10.1038/s42003-020-01453-8
摘要
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 Gα q and Gα 12/13 activity and their downstream effectors, while having no effect on G i/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.
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