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Updated: Jul 3, 2026
Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells
Published on: May 22, 2014
A potent NLRP3 inhibitor effective against both MCC950-sensitive and -resistant inflammation
Wonyoung Kim1, Soyeon Kim1, Hawon Woo1
1Department of Biological Sciences, College of Natural Science, Seoul National University, Seoul 08826, South Korea.
Abstract:
The nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome detects a broad spectrum of pathogen- and damage-associated molecular patterns (PAMPs and DAMPs), initiating inflammatory responses through caspase-1 activation and interleukin (IL)-1β/IL-18 release. Dysregulated NLRP3 activation is implicated in a range of diseases, including infectious diseases, autoinflammatory disorders, metabolic disorders, and cancer, making it an attractive therapeutic target. Here, we identify ZAP-180013 as a potent and selective small-molecule inhibitor of NLRP3 through high-throughput chemical screening. Molecular docking predicted that ZAP-180013 interacts with histidine 698 (H698) in NLRP3; this was validated by H698A substitution, which abolished binding and inhibitory activity. ZAP-180013 effectively inhibited inflammasome activation in human myeloid cells, including those carrying MCC950-resistant NLRP3 mutations. In vivo, systemic administration of ZAP-180013 ameliorated psoriasiform skin inflammation and protected against lipopolysaccharide (LPS)-induced cytokine responses in mice. These findings establish ZAP-180013 as a potent and selective NLRP3 inhibitor with translational potential in both MCC950-sensitive and -resistant inflammatory disease settings.
Insights
Researchers discovered ZAP-180013, a potent small-molecule inhibitor of the NLRP3 inflammasome. This compound effectively reduces inflammation in cellular and animal models, showing promise for treating inflammatory diseases.
Area of Science:
- Immunology
- Molecular Biology
- Pharmacology
Background:
- The NLRP3 inflammasome is a key mediator of inflammatory responses, detecting pathogen- and damage-associated molecular patterns.
- Dysregulated NLRP3 activation is linked to various diseases, including inflammatory disorders, metabolic diseases, and cancer.
- Targeting NLRP3 offers a therapeutic strategy for numerous inflammatory conditions.
Purpose of the Study:
- To identify and characterize novel small-molecule inhibitors of the NLRP3 inflammasome.
- To evaluate the efficacy of ZAP-180013 in preclinical models of inflammation.
Main Methods:
- High-throughput chemical screening to identify NLRP3 inhibitors.
- Molecular docking and site-directed mutagenesis to determine the binding site of ZAP-180013.
- In vitro assays using human myeloid cells to assess inflammasome inhibition.
- In vivo studies in mouse models to evaluate therapeutic potential.
Main Results:
- ZAP-180013 was identified as a potent and selective NLRP3 inhibitor.
- Molecular docking and experimental validation confirmed ZAP-180013 binds to H698 in NLRP3.
- ZAP-180013 inhibited NLRP3 inflammasome activation in human cells, including MCC950-resistant variants.
- Systemic administration of ZAP-180013 reduced skin inflammation and LPS-induced cytokine responses in mice.
Conclusions:
- ZAP-180013 is a potent and selective NLRP3 inhibitor with demonstrated efficacy in preclinical models.
- This inhibitor shows potential for treating inflammatory diseases, including those resistant to other therapies.
- ZAP-180013 represents a promising therapeutic candidate for NLRP3-mediated inflammatory conditions.
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