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Published on: May 21, 2018
Discovery of a Covalent Inhibitor of Pro-Caspase-1 Zymogen Blocking NLRP3 Inflammasome Activation and Pyroptosis
Dongyi Cao1,2, Ruiying Xi1,3, Hongye Li4
1Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
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.
Insights
A novel compound, CIB-1476, effectively inhibits caspase-1 activity and inflammasome activation, offering a new therapeutic strategy for inflammatory diseases. This irreversible inhibitor targets pro-caspase-1, providing durable anti-inflammatory effects.
Area of Science:
- Immunology
- Molecular Biology
- Drug Discovery
Background:
- Caspase-1 is crucial for innate immunity, regulating inflammatory cytokine production and pyroptosis via inflammasome activation.
- Direct inhibition of caspase-1 enzymatic activity is insufficient to control inflammation due to its enzyme-independent functions.
- NLRP3 inflammasome and gasdermin-D-mediated pyroptosis are key inflammatory pathways.
Purpose of the Study:
- To identify a novel inhibitor targeting caspase-1 with durable anti-inflammatory effects.
- To investigate the mechanism of action of the identified compound.
- To evaluate the therapeutic potential of the compound in preclinical models.
Main Methods:
- Screening for compounds that inhibit caspase-1 activity.
- Characterization of CIB-1476 as an irreversible covalent inhibitor targeting pro-caspase-1.
- Chemoproteomic profiling to confirm target engagement.
- In vivo studies in mice to assess therapeutic efficacy in inflammasome activation models.
Main Results:
- CIB-1476 potently inhibits caspase-1 activity and suppresses NLRP3 inflammasome assembly and activation.
- CIB-1476 acts as an irreversible covalent inhibitor, binding to Cys285 and Cys397 of pro-caspase-1.
- The compound demonstrates durable suppression of both enzyme-dependent IL-1β production and enzyme-independent NF-κB activation.
- CIB-1476 exhibits significant therapeutic effects in mouse models of inflammasome activation.
Conclusions:
- CIB-1476 is a potent, irreversible inhibitor of caspase-1 with broad anti-inflammatory effects.
- The compound effectively targets both enzymatic and non-enzymatic functions of caspase-1.
- CIB-1476 represents a promising novel therapeutic strategy for inflammatory conditions driven by inflammasome activation.
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