PMID- 35183871 OWN - NLM STAT- MEDLINE DCOM- 20220316 LR - 20220316 IS - 1768-3254 (Electronic) IS - 0223-5234 (Linking) VI - 232 DP - 2022 Mar 15 TI - Discovery of a novel and potent inhibitor with differential species-specific effects against NLRP3 and AIM2 inflammasome-dependent pyroptosis. PG - 114194 LID - S0223-5234(22)00096-4 [pii] LID - 10.1016/j.ejmech.2022.114194 [doi] AB - The NLRP3 inflammasome, which regulated a proinflammatory programmed cell death form termed pyroptosis, is involved in the pathological process of various human diseases, such as multiple sclerosis, type 2 diabetes, and gout. Thus, compounds inhibiting activation of the NLRP3 inflammasome can be promising treatments for these diseases. In this study, we conducted a phenotypic screening against NLRP3-dependent pyroptosis and discovered the hit compound 1, which showed moderate antipyroptotic activity. Chemistry efforts to improve potency of 1 resulted in a novel compound 59 (J114), which exhibited a half-maximal inhibitory concentration (IC(50)) of 0.077 +/- 0.008 muM against cell pyroptosis. Interestingly, unlike all pyroptosis inhibitors currently reported, the activity of J114 showed significant differences in human- and mouse-derived cells. The IC(50) of J114-mediated inhibition of IL-1beta secretion by human THP-1 macrophages was 0.098 muM, which was nearly 150-fold and 500-fold more potent than that of J774A.1 (14.62 muM) and bone marrow-derived macrophages (BMDMs) (48.98 muM), respectively. Further studies showed that J114 displayed remarkable inhibitory activity against NLRP3- and AIM2-but not NLRC4-dependent activation of caspase-1 and the release of IL-1beta in human THP-1 macrophages. Mechanistically, J114 disturbed the interaction of NLRP3 or AIM2 with the adaptor protein ASC and inhibited ASC oligomerization. Overall, our study identified a unique molecule that inhibits NLRP3 and AIM2 inflammasome activation and has species differences, which is worthy of further research to understand the differential regulation of the NLRP3 and AIM2 inflammasomes in humans and mice. CI - Copyright (c) 2022 Elsevier Masson SAS. All rights reserved. FAU - Jiao, Yan AU - Jiao Y AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, And Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan, 610041, China. FAU - Nan, Jinshan AU - Nan J AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, And Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan, 610041, China. FAU - Mu, Bo AU - Mu B AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, And Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan, 610041, China; Basic Medical College of North Sichuan Medical College, Nanchong, Sichuan, 637000, China. FAU - Zhang, Yun AU - Zhang Y AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, And Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan, 610041, China; Research Laboratory of Macular Disease, Department of Ophthalmology, West China Hospital, Sichuan University, Sichuan, 610041, China. FAU - Zhou, Nenghua AU - Zhou N AD - Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan, 610041, China. FAU - Yang, Shunhua AU - Yang S AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, And Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan, 610041, China. FAU - Zhang, Shanshan AU - Zhang S AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, And Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan, 610041, China. FAU - Lin, Wanting AU - Lin W AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, And Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan, 610041, China. FAU - Wang, Falu AU - Wang F AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, And Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan, 610041, China. FAU - Xia, Anjie AU - Xia A AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, And Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan, 610041, China. FAU - Cao, Zhixing AU - Cao Z AD - State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Sichuan, 610041, China. FAU - Chen, Pei AU - Chen P AD - Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan, 610041, China. FAU - Pan, Zhiling AU - Pan Z AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, And Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan, 610041, China. FAU - Lin, Guifeng AU - Lin G AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, And Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan, 610041, China. FAU - Pan, Shulei AU - Pan S AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, And Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan, 610041, China. FAU - Bin, Huachao AU - Bin H AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, And Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan, 610041, China. FAU - Li, Linli AU - Li L AD - Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan, 610041, China. Electronic address: lilinli@scu.edu.cn. FAU - Yang, Shengyong AU - Yang S AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, And Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan, 610041, China. Electronic address: yangsy@scu.edu.cn. LA - eng PT - Journal Article DEP - 20220211 PL - France TA - Eur J Med Chem JT - European journal of medicinal chemistry JID - 0420510 RN - 0 (Aim2 protein, mouse) RN - 0 (DNA-Binding Proteins) RN - 0 (Inflammasomes) RN - 0 (Interleukin-1beta) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Nlrp3 protein, mouse) SB - IM MH - Animals MH - DNA-Binding Proteins MH - *Diabetes Mellitus, Type 2 MH - *Inflammasomes MH - Interleukin-1beta/metabolism MH - Mice MH - Mice, Inbred C57BL MH - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism MH - Pyroptosis MH - Species Specificity OTO - NOTNLM OT - AIM2 inflammasome OT - ASC oligomerization OT - NLRP3 inflammasome OT - Pyroptosis inhibitor OT - Species differences COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/02/21 06:00 MHDA- 2022/03/17 06:00 CRDT- 2022/02/20 20:33 PHST- 2021/12/28 00:00 [received] PHST- 2022/02/08 00:00 [revised] PHST- 2022/02/08 00:00 [accepted] PHST- 2022/02/21 06:00 [pubmed] PHST- 2022/03/17 06:00 [medline] PHST- 2022/02/20 20:33 [entrez] AID - S0223-5234(22)00096-4 [pii] AID - 10.1016/j.ejmech.2022.114194 [doi] PST - ppublish SO - Eur J Med Chem. 2022 Mar 15;232:114194. doi: 10.1016/j.ejmech.2022.114194. Epub 2022 Feb 11.