Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders

By Hua Jiang, Hongbin He, Yun Chen, Wei Huang, Jinbo Cheng, Jin Ye, Aoli Wang, Jin-Hui Tao, Chao Wang, Qingsong Liu and 4 more. Journal of Experimental Medicine, 2017

677 citations recorded by the source corpus.

The NLRP3 inflammasome has been implicated in the pathogenesis of a wide variety of human diseases. A few compounds have been developed to inhibit NLRP3 inflammasome activation, but compounds directly and specifically targeting NLRP3 are still not available, so it is unclear whether NLRP3 itself can be targeted to prevent or treat diseases. Here we show that the compound CY-09 specifically blocks NLRP3 inflammasome activation. CY-09 directly binds to the ATP-binding motif of NLRP3 NACHT domain and inhibits NLRP3 ATPase activity, resulting in the suppression of NLRP3 inflammasome assembly and activation. Importantly, treatment with CY-09 shows remarkable therapeutic effects on mouse models of cryopyrin-associated autoinflammatory syndrome (CAPS) and type 2 diabetes. Furthermore, CY-09 is active ex vivo for monocytes from healthy individuals or synovial fluid cells from patients with gout. Thus, our results provide a selective and direct small-molecule inhibitor for NLRP3 and indicate that NLRP3 can be targeted in vivo to combat NLRP3-driven diseases.

Subfields: Molecular Biology, Nephrology

View Paper: https://www.semanticscholar.org/paper/13869888d0074be3253c0d3f8f644351d0969b77

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In Molecular Biology

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Citations in the corpus

• An update on the regulatory mechanisms of NLRP3 inflammasome activation (2021, background): “The CFTR(inh)-172 analog CY09 also inhibits NLRP3 ATPase activity by directly binding to the ATP-binding motif of the NLRP3 NACHT domain.(249) Prominent therapeutic effects were observed in mouse models of CAPS and T2DM and in monocytes of gout patients(249) treated with CY-09.”
• Inflammation and atherosclerosis: signaling pathways and therapeutic intervention (2022, background): “CY-09 directly interacts with the NACHT domain and disrupts ATP binding to NLRP3, which shows excellent preventive and therapeutic effects in mouse models.(196) The smallmolecule inhibitors VX-765, a caspase-1 inhibitor prodrug activated by intracellular esterases, can mitigate atherosclerosis in mi”