2. Academic Validation
  3. Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders

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

  • J Exp Med. 2017 Nov 6;214(11):3219-3238. doi: 10.1084/jem.20171419.
Hua Jiang 1 2 3,  Hongbin He 1,  Yun Chen 4,  Wei Huang 4,  Jinbo Cheng 1,  Jin Ye 1,  Aoli Wang 1 5,  Jinhui Tao 6,  Chao Wang 1,  Qingsong Liu 1 5,  Tengchuan Jin 1,  Wei Jiang 7 3,  Xianming Deng 8,  Rongbin Zhou 9 2 3
Affiliations

Affiliations

  • 1 Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China.
  • 2 Innovation Center for Cell Signaling Network, University of Science and Technology of China, Hefei, China.
  • 3 Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, China.
  • 4 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
  • 5 High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui, China.
  • 6 Department of Rheumatology and Immunology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China.
  • 7 Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China ustcjw@ustc.edu.cn.
  • 8 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China xmdeng@xmu.edu.cn.
  • 9 Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China zrb1980@ustc.edu.cn.
PMID: 29021150 DOI: 10.1084/jem.20171419
Abstract

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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