2024年1月3日，《中国药理学报》杂志在线发表了温州医科大学Guang Liang等研究人员合作的最新成果。该研究表明，旋覆花内酯作为一种新型NLRP3抑制剂可抑制巨噬细胞中炎性小体的激活，并缓解小鼠NLRP3相关疾病的病情。

研究人员表示，NLRP3炎性小体的过度激活会诱发促炎细胞因子的产生并推动病理过程。药物抑制NLRP3是治疗炎症性疾病的明确策略。迄今为止，美国食品及药物管理局尚未批准任何专门针对NLRP3的药物用于临床。研究人员旨在发现可抑制NLRP3介导焦亡的新型NLRP3抑制剂。

研究人员从公司内部的天然产物库中筛选了95种对LPS+ATP挑战的BMDM分泌IL-1β有抑制作用的天然产物，发现旋覆花内酯的抑制作用最强，IC₅₀值为3.630 µM。研究人员发现，旋覆花内酯（1、5、10 µM）剂量依赖性地抑制了小鼠和人类巨噬细胞中已切割的Caspase-1（p20）和成熟的IL-1β的分泌，并抑制了NLRP3介导的焦亡。

研究人员证实，旋覆花内酯通过中断NLRP3的组装步骤，特别是NLRP3与NEK7之间的相互作用，特异性地抑制了NLRP3炎性体在BMDM中的激活步骤。研究人员发现旋覆花内酯能直接与NLRP3 NACHT结构域的Arg335和Gly271结合。

附：英文原文

Title: Britannin as a novel NLRP3 inhibitor, suppresses inflammasome activation in macrophages and alleviates NLRP3-related diseases in mice

Author: Shao, Jing-jing, Li, Wei-feng, Sun, Jin-feng, Zhuang, Zai-shou, Min, Ju-lian, Long, Xiao-hong, Wu, Gao-jun, Xu, Hao-wen, Liang, Guang

Issue&Volume: 2024-01-03

Abstract: Overactivation of the NLRP3 inflammasomes induces production of pro-inflammatory cytokines and drives pathological processes. Pharmacological inhibition of NLRP3 is an explicit strategy for the treatment of inflammatory diseases. Thus far no drug specifically targeting NLRP3 has been approved by the FDA for clinical use. This study was aimed to discover novel NLRP3 inhibitors that could suppress NLRP3-mediated pyroptosis. We screened 95 natural products from our in-house library for their inhibitory activity on IL-1β secretion in LPS+ATP-challenged BMDMs, found that Britannin exerted the most potent inhibitory effect with an IC50 value of 3.630μM. We showed that Britannin (1, 5, 10μM) dose-dependently inhibited secretion of the cleaved Caspase-1 (p20) and the mature IL-1β, and suppressed NLRP3-mediated pyroptosis in both murine and human macrophages. We demonstrated that Britannin specifically inhibited the activation step of NLRP3 inflammasome in BMDMs via interrupting the assembly step, especially the interaction between NLRP3 and NEK7. We revealed that Britannin directly bound to NLRP3 NACHT domain at Arg335 and Gly271. Moreover, Britannin suppressed NLRP3 activation in an ATPase-independent way, suggesting it as a lead compound for design and development of novel NLRP3 inhibitors. In mouse models of MSU-induced gouty arthritis and LPS-induced acute lung injury (ALI), administration of Britannin (20mg/kg, i.p.) significantly alleviated NLRP3-mediated inflammation; the therapeutic effects of Britannin were dismissed by NLRP3 knockout. In conclusion, Britannin is an effective natural NLRP3 inhibitor and a potential lead compound for the development of drugs targeting NLRP3.

DOI: 10.1038/s41401-023-01212-5

Source: https://www.nature.com/articles/s41401-023-01212-5