Discovery of Selective P2Y<sub>6</sub>R Antagonists with High Affinity and <i>In Vivo</i> Efficacy for Inflammatory Disease Therapy
Yifan Zhu, Mengze Zhou, Xiangyu Cheng, Hui Wang, Yehong Li, Yueyue Guo, Yaxuan Wang, Sheng Tian, Tianqi Mao, Zhoudong Zhang, Duxin Li, Qinghua Hu, Huanqiu Li
Abstract
As a member of purinoceptors, the P2Y 6 receptor (P2Y 6 R) plays a crucial role in modulating immune signals and has been considered as a potential therapeutic target for inflammatory diseases. On the basis of the speculated probable conformation and binding determinants of P2Y 6 R, a hierarchical strategy that combines virtual screening, bioassays, and chemical optimization was presented. A potent P2Y 6 R antagonist (compound 50 ) was identified to possess excellent antagonistic activity (IC 50 = 5.914 nM) and high selectivity. In addition, binding assays and chemical pull-down experiments confirmed that compound 50 was nicely bound to P2Y 6 R. Notably, compound 50 could effectively ameliorate DSS-induced ulcerative colitis in mice through inhibiting the activation of NLRP3 inflammasome in colon tissues. Moreover, treatment with compound 50 reduced LPS-induced pulmonary edema and infiltration of inflammatory cells in mice. These findings suggest that compound 50 could serve as a specific P2Y 6 R antagonist for treating inflammatory diseases and deserve further optimization studies.