Key Laboratory of Molecular Target & Clinical Pharmacology and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China.
Key Laboratory of Molecular Target & Clinical Pharmacology and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China.
Eur J Med Chem. 2021 Jul 5;219:113417. doi: 10.1016/j.ejmech.2021.113417. Epub 2021 Apr 1.
NLRP3 inflammasome activation plays a critical role in inflammation and its related disorders. Herein we report a hit-to-lead effort resulting in the discovery of a novel and potent class of NLRP3 inflammasome inhibitors. Among these, the most potent lead 40 exhibited improved inhibitory potency and almost no toxicity. Further mechanistic study indicated that compound 40 inhibited the NLRP3 inflammasome activation via suppressing ROS production. More importantly, treatment with 40 showed remarkable therapeutic effects on LPS-induced sepsis and DSS-induced colitis. This study encourages further development of more potent inhibitors based on this chemical scaffold and provides a chemical tool to identify its cellular binding target.
NLRP3 炎性小体的激活在炎症及其相关疾病中起着关键作用。在此，我们报告了一项从命中到先导的努力，从而发现了一类新型有效的 NLRP3 炎性小体抑制剂。在这些抑制剂中，最有效的先导化合物 40 表现出改善的抑制效力和几乎没有毒性。进一步的机制研究表明，化合物 40 通过抑制 ROS 产生来抑制 NLRP3 炎性小体的激活。更重要的是，用 40 治疗可显著改善 LPS 诱导的脓毒症和 DSS 诱导的结肠炎。这项研究鼓励进一步开发基于该化学结构的更有效的抑制剂，并提供了一种化学工具来鉴定其细胞结合靶标。
