Discovery of a Covalent Inhibitor of Pro-Caspase-1 Zymogen Blocking NLRP3 Inflammasome Activation and Pyroptosis,Journal of Medicinal Chemistry

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Discovery of a Covalent Inhibitor of Pro-Caspase-1 Zymogen Blocking NLRP3 Inflammasome Activation and Pyroptosis
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-19 , DOI: 10.1021/acs.jmedchem.4c01558
Dongyi Cao _{1,

2} , Ruiying Xi _{1,

3} , Hongye Li ₄ , Zhonghui Zhang ₅ , Xiaoke Shi _{1,

3} , Shanshan Li _{1,

3} , Yujie Jin _{1,

3} , Wanli Liu ₆ , Guolin Zhang ₁ , Xiaohua Liu ₄ , Shunxi Dong ₄ , Xiaoming Feng ₄ , Fei Wang ₁

Affiliation

Caspase-1 plays a central role in innate immunity, as its activation by inflammasomes induces the production of proinflammatory cytokines and pyroptosis. However, specific inhibition of the enzymatic activity of this protease is not effective in suppressing inflammation, owing to its enzyme-independent function. Herein, we identified a cyclohexenyl isothiocyanate compound (CIB-1476) that potently inhibited caspase-1 activity and suppressed the assembly and activation of the NLRP3 inflammasome and gasdermin-D-mediated pyroptosis. Mechanistically, CIB-1476 directly targeted pro-caspase-1 as an irreversible covalent inhibitor by binding to Cys285 and Cys397, resulting in more durable anti-inflammatory effects in the suppression of enzyme-dependent IL-1β production and enzyme-independent nuclear factor κB activation. Chemoproteomic profiling demonstrated the engagement of CIB-1476 with caspase-1. CIB-1476 showed potent therapeutic effects by suppressing inflammasome activation in mice, which was abolished in Casp1^–/– mice. These results warrant further development of CIB-1476 along with its analogues as a novel strategy for caspase-1 inhibitors.

中文翻译：

发现一种可阻断 NLRP3 炎症小体激活和焦亡的 Pro-Caspase-1 酶原共价抑制剂

Caspase-1 在先天免疫中发挥着核心作用，因为它被炎症小体激活会诱导促炎细胞因子和细胞焦亡的产生。然而，由于其不依赖于酶的功能，特异性抑制这种蛋白酶的酶活性并不能有效抑制炎症。在此，我们鉴定了一种环己烯基异硫氰酸酯化合物 ( CIB-1476 )，它能有效抑制 caspase-1 活性并抑制 NLRP3 炎症小体的组装和激活以及gasdermin-D 介导的细胞焦亡。从机制上讲， CIB-1476通过与 Cys285 和 Cys397 结合，作为不可逆共价抑制剂直接靶向 pro-caspase-1，从而在抑制酶依赖性 IL-1β 产生和酶独立核因子 κB 的抑制中产生更持久的抗炎作用激活。化学蛋白质组学分析证明了CIB-1476与 caspase-1 的结合。 CIB-1476通过抑制小鼠炎症小体激活而显示出有效的治疗效果，而在Casp1 ^–/–小鼠中，炎症小体激活被消除。这些结果保证了CIB-1476及其类似物作为 caspase-1 抑制剂的新策略的进一步开发。

更新日期：2024-08-19

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