Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity

Hongbin He, Hua Jiang, Yun Chen, Jin Ye, Aoli Wang, Chao Wang, Qingsong Liu, Gaolin Liang, Xianming Deng (), Wei Jiang () and Rongbin Zhou ()
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Hongbin He: the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China
Hua Jiang: the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China
Yun Chen: Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen
Jin Ye: the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China
Aoli Wang: Chinese Academy of Sciences
Chao Wang: the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China
Qingsong Liu: Chinese Academy of Sciences
Gaolin Liang: Hefei National Laboratory for Physical Sciences at Microscale, Department of Chemistry, University of Science and Technology of China
Xianming Deng: Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen
Wei Jiang: the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China
Rongbin Zhou: the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract Oridonin (Ori) is the major active ingredient of the traditional Chinese medicinal herb Rabdosia rubescens and has anti-inflammatory activity, but the target of Ori remains unknown. NLRP3 is a central component of NLRP3 inflammasome and has been involved in a wide variety of chronic inflammation-driven human diseases. Here, we show that Ori is a specific and covalent inhibitor for NLRP3 inflammasome. Ori forms a covalent bond with the cysteine 279 of NLRP3 in NACHT domain to block the interaction between NLRP3 and NEK7, thereby inhibiting NLRP3 inflammasome assembly and activation. Importantly, Ori has both preventive or therapeutic effects on mouse models of peritonitis, gouty arthritis and type 2 diabetes, via inhibition of NLRP3 activation. Our results thus identify NLRP3 as the direct target of Ori for mediating Ori’s anti-inflammatory activity. Ori could serve as a lead for developing new therapeutics against NLRP3-driven diseases.

Date: 2018
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DOI: 10.1038/s41467-018-04947-6

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