Costunolide covalently targets NACHT domain of NLRP3 to inhibit inflammasome activation and alleviate NLRP3-driven inflammatory diseases.
10.1016/j.apsb.2022.09.014
- Author:
Haowen XU
1
;
Jiahao CHEN
1
;
Pan CHEN
1
;
Weifeng LI
1
;
Jingjing SHAO
1
;
Shanshan HONG
1
;
Yi WANG
1
;
Lingfeng CHEN
2
;
Wu LUO
1
;
Guang LIANG
1
Author Information
1. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
2. School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou 311399, China.
- Publication Type:Journal Article
- Keywords:
Costunolide;
Gouty arthritis;
Inflammation;
Molecular target;
NACHT domain;
NLRP3 inflammasome;
Ulcerative colitis;
α-Methylene-γ-butyrolactone
- From:
Acta Pharmaceutica Sinica B
2023;13(2):678-693
- CountryChina
- Language:English
-
Abstract:
The NLRP3 inflammasome's core and most specific protein, NLRP3, has a variety of functions in inflammation-driven diseases. Costunolide (COS) is the major active ingredient of the traditional Chinese medicinal herb Saussurea lappa and has anti-inflammatory activity, but the principal mechanism and molecular target of COS remain unclear. Here, we show that COS covalently binds to cysteine 598 in NACHT domain of NLRP3, altering the ATPase activity and assembly of NLRP3 inflammasome. We declare COS's great anti-inflammasome efficacy in macrophages and disease models of gouty arthritis and ulcerative colitis via inhibiting NLRP3 inflammasome activation. We also reveal that the α-methylene-γ-butyrolactone motif in sesquiterpene lactone is the certain active group in inhibiting NLRP3 activation. Taken together, NLRP3 is identified as a direct target of COS for its anti-inflammasome activity. COS, especially the α-methylene-γ-butyrolactone motif in COS structure, might be used to design and produce novel NLRP3 inhibitors as a lead compound.
