2. Academic Validation
  3. Discovery of a Covalent Inhibitor of Pro-Caspase-1 Zymogen Blocking NLRP3 Inflammasome Activation and Pyroptosis

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

  • J Med Chem. 2024 Sep 12;67(17):15873-15891. 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
Affiliations

Affiliations

  • 1 Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
  • 2 Department of Pharmacy, Kunming Municipal Hospital of Traditional Chinese Medicine, Kunming 650500, China.
  • 3 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4 Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China.
  • 5 School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 511400, China.
  • 6 State Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, Beijing Advanced Innovation Center for Structural Biology, Beijing Key Lab for Immunological Research on Chronic Diseases, Beijing 100084, China.
PMID: 39159426 DOI: 10.1021/acs.jmedchem.4c01558
Abstract

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.

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