Identification and Validation of PKR as a Direct Target for the Novel Sulfonamide-Substituted Tetrahydroquinoline Nonselective Inhibitor of the NLRP3 Inflammasome,Journal of Medicinal Chemistry

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Identification and Validation of PKR as a Direct Target for the Novel Sulfonamide-Substituted Tetrahydroquinoline Nonselective Inhibitor of the NLRP3 Inflammasome
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-06-10 , DOI: 10.1021/acs.jmedchem.4c00343
Fan Yang _{1,

2} , Zhen Dai _{1,

2,

3} , Ming-Yue Xue _{1,

2} , Xiao-Yi Chen _{1,

2} , Juan Liu _{1,

2} , Li Wang _{1,

2} , Li-Li Xu _{1,

2} , Bin Di _{1,

2}

Affiliation

The NLRP3 inflammasome is a critical component of the innate immune system. The persistent abnormal activation of the NLRP3 inflammasome is implicated in numerous human diseases. Herein, sulfonamide-substituted tetrahydroquinoline derivative S-9 was identified as the most promising NLRP3 inhibitor, without obvious cytotoxicity. In vitro, S-9 inhibited the priming and activation stages of the NLRP3 inflammasome. Incidentally, we also observed that S-9 had inhibitory effects on the NLRC4 and AIM2 inflammasomes. To elucidate the multiple anti-inflammatory activities of S-9, photoaffinity probe P-2, which contained a photoaffinity label and a functional handle, was developed for target identification by chemical proteomics. We identified PKR as a novel target of S-9 in addition to NLRP3 by target fishing. Furthermore, S-9 exhibited a significant anti-neuroinflammatory effect in vivo. In summary, our findings show that S-9 is a promising lead compound targeting both PKR and NLRP3 that could emerge as a molecular tool for treating inflammasome-related diseases.

中文翻译：

鉴定和验证 PKR 作为新型磺酰胺取代的四氢喹啉非选择性 NLRP3 炎症小体抑制剂的直接靶点

NLRP3 炎症小体是先天免疫系统的重要组成部分。 NLRP3 炎性体的持续异常激活与许多人类疾病有关。在此，磺酰胺取代的四氢喹啉衍生物S-9被认为是最有前途的NLRP3抑制剂，且没有明显的细胞毒性。在体外， S-9抑制 NLRP3 炎性体的启动和激活阶段。顺便说一句，我们还观察到S-9对NLRC4和AIM2炎症小体有抑制作用。为了阐明S-9的多种抗炎活性，开发了包含光亲和标记和功能手柄的光亲和探针P-2 ，用于化学蛋白质组学的靶点识别。我们通过靶向捕捞确定了 PKR 是除 NLRP3 之外的S-9的新靶点。此外， S-9在体内表现出显着的抗神经炎症作用。总之，我们的研究结果表明， S-9是一种有前途的针对 PKR 和 NLRP3 的先导化合物，可以作为治疗炎症小体相关疾病的分子工具。

更新日期：2024-06-10

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