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Z1456467176 通过变构调节 P2X7R 以抑制 NLRP3 炎性小体激活来缓解痛风性关节炎。

Z1456467176 alleviates gouty arthritis by allosterically modulating P2X7R to inhibit NLRP3 inflammasome activation.

作者信息

Li Xiaoling, Liu Yiming, Luo Chengyu, Tao Jinhui

机构信息

Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

出版信息

Front Pharmacol. 2022 Aug 16;13:979939. doi: 10.3389/fphar.2022.979939. eCollection 2022.

DOI:10.3389/fphar.2022.979939
PMID:36052144
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9424684/
Abstract

NLRP3 inflammasome activation is a central process in initiating gout flares. The unique conformational rearrangement of the P2X7 receptor (P2X7R) upon ATP binding is critical for the activation of the NLRP3 inflammasome. However, studies on allosteric modulation of P2X7R in gout treatment are limited. Here, we aimed to investigate the therapeutic implications of targeting P2X7R in gout by designing a P2X7R allosteric inhibitor and validating the inhibitory function on NLRP3 inflammasome activation. Through virtual screening, we identified Z1456467176 (N-{3-[(2-aminoethyl) sulfamoyl] phenyl}-2-methyl-3-[3-(trifluoromethyl) phenyl] propanamide hydrochloride) bound to the drug-binding pocket as a potential antagonist of P2X7R. In functional assays, ATP- or BzATP-induced P2X7R function was assessed in HEK-293T cells overexpressing hP2X7R (dye uptake assay) and macrophages (IL-1β release assay). Z1456467176 exhibited a stable and significant P2X7R inhibitory effect. Importantly, in MSU crystal-induced gout, the presence and involvement of ATP were confirmed. Z1456467176 blocked ATP-induced activation of the NLRP3-caspase-1-IL-1β pathway and exerted promising effects in reducing gouty joint inflammation in rats. In addition, molecular docking and molecular dynamics simulation studies showed that the P27XR protein conformation was remodeled by Z1456467176 binding. Collectively, our results provide a potent P2X7R allosteric inhibitor that facilitates the remission of MSU crystal-induced gout inflammation by inhibiting NLRP3 inflammasome activation, suggesting that allosteric inhibition of P2X7R represents a new direction in gout treatment.

摘要

NLRP3炎性小体激活是引发痛风发作的核心过程。ATP结合后P2X7受体（P2X7R）独特的构象重排对于NLRP3炎性小体的激活至关重要。然而，关于痛风治疗中P2X7R变构调节的研究有限。在此，我们旨在通过设计一种P2X7R变构抑制剂并验证其对NLRP3炎性小体激活的抑制功能，来研究靶向P2X7R在痛风治疗中的意义。通过虚拟筛选，我们确定与药物结合口袋结合的Z1456467176（N-{3-[(2-氨基乙基)氨磺酰基]苯基}-2-甲基-3-[3-(三氟甲基)苯基]丙酰胺盐酸盐）为P2X7R的潜在拮抗剂。在功能实验中，在过表达hP2X7R的HEK-293T细胞（染料摄取实验）和巨噬细胞（IL-1β释放实验）中评估ATP或BzATP诱导的P2X7R功能。Z1456467176表现出稳定且显著的P2X7R抑制作用。重要的是，在MSU晶体诱导的痛风中，证实了ATP的存在和参与。Z1456467176阻断了ATP诱导的NLRP3-半胱天冬酶-1-IL-1β途径的激活，并在减轻大鼠痛风性关节炎症方面发挥了有前景的作用。此外，分子对接和分子动力学模拟研究表明，Z1456467176的结合重塑了P27XR蛋白构象。总的来说，我们的结果提供了一种有效的P2X7R变构抑制剂，其通过抑制NLRP3炎性小体激活促进MSU晶体诱导的痛风炎症缓解，表明P2X7R的变构抑制代表了痛风治疗的一个新方向。

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