机构：[1]Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu 610041, China.四川大学华西医院[2]Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.四川大学华西医院[3]School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.[4]Chengdu Zenitar Biomedical Technology Co., Ltd., Chengdu 610041, China.[5]Division of Thyroid Surgery, Department of General Surgery and Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.四川大学华西医院
The NLRP3 inflammasome has been recognized as a promising therapeutic target in drug discovery for inflammatory diseases. Our initial research identified a natural sesquiterpene isoalantolactone (IAL) as the active scaffold targeting NLRP3 inflammasome. To improve its activity and metabolic stability, a total of 64 IAL derivatives were designed and synthesized. Among them, compound 49 emerged as the optimal lead, displaying the most potent inhibitory efficacy on nigericin-induced IL-1β release in THP-1 cells, with an IC50 value of 0.29 μM, approximately 27-fold more potent than that of IAL (IC50: 7.86 μM), and exhibiting higher metabolic stability. Importantly, 49 remarkably improved DSS-induced ulcerative colitis in vivo. Mechanistically, we demonstrated that 49 covalently bound to cysteine 279 in the NACHT domain of NLRP3, thereby inhibiting the assembly and activation of NLRP3 inflammasome. These results provided compelling evidence to further advance the development of more potent NLRP3 inhibitors based on this scaffold.
基金：
National Natural
Sciences Foundation of China (82174077 and 81903500) and
the Science and Technology Department of Sichuan Province
(2023NSFSC1772 and 2021YFS0230).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2023]版：
大类|1 区医学
小类|1 区药物化学
最新[2023]版：
大类|1 区医学
小类|1 区药物化学
第一作者：
第一作者机构：[1]Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu 610041, China.
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Zhao Min,Ye Neng,Liu Ling,et al.Novel Isoalantolactone-Based Derivatives as Potent NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization[J].Journal Of Medicinal Chemistry.2024,doi:10.1021/acs.jmedchem.4c00357.
APA：
Zhao Min,Ye Neng,Liu Ling,Zhang Rui-Jia,Li Na...&Ye Hao-Yu.(2024).Novel Isoalantolactone-Based Derivatives as Potent NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization.Journal Of Medicinal Chemistry,,
MLA：
Zhao Min,et al."Novel Isoalantolactone-Based Derivatives as Potent NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization".Journal Of Medicinal Chemistry .(2024)
医学