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

The Journal of experimental medicine (2017-10-13)
Hua Jiang, Hongbin He, Yun Chen, Wei Huang, Jinbo Cheng, Jin Ye, Aoli Wang, Jinhui Tao, Chao Wang, Qingsong Liu, Tengchuan Jin, Wei Jiang, Xianming Deng, Rongbin Zhou
RESUMEN

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.

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Sigma-Aldrich
DL-Sulforaphane, ≥90% (HPLC), synthetic, liquid
Sigma-Aldrich
Monoclonal ANTI-FLAG® antibody produced in rabbit, clone SIG1-25, ascites fluid
Sigma-Aldrich
Anti-VSV-G antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
CY-09, ≥98% (HPLC)

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