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Science Advances

Science Advances

IF: 11.7
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NU6300 covalently reacts with cysteine-191 of gasdermin D to block its cleavage and palmitoylation

Published:7 February 2024 DOI: 10.1126/sciadv.adi9284 PMID: 38324683
Xueqin Jiang, Xinlu Zhang, Xiaoying Cai, Na Li, Hongyu Zheng, Minghai Tang, Jiangli Zhu, Kaiyue Su, Ruijia Zhang, Neng Ye, Jing Peng, Min Zhao, Wenshuang Wu, Jianhong Yang, Haoyu Ye

Abstract

Gasdermin D (GSDMD) serves as a vital mediator of inflammasome-driven pyroptosis. In our study, we have identified NU6300 as a specific GSDMD inhibitor that covalently interacts with cysteine-191 of GSDMD, effectively blocking its cleavage while not affecting earlier steps such as ASC oligomerization and caspase-1 processing in AIM2- and NLRC4-mediated inflammation. On the contrary, NU6300 robustly inhibits these earlier steps in NLRP3 inflammasome, confirming a unique feedback inhibition effect in the NLRP3-GSDMD pathway upon GSDMD targeting. Our study reveals a previously undefined mechanism of GSDMD inhibitors: NU6300 impairs the palmitoylation of both full-length and N-terminal GSDMD, impeding the membrane localization and oligomerization of N-terminal GSDMD. In vivo studies further demonstrate the efficacy of NU6300 in ameliorating dextran sodium sulfate–induced colitis and improving survival in lipopolysaccharide-induced sepsis. Overall, these findings highlight the potential of NU6300 as a promising lead compound for the treatment of inflammatory diseases.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Necrosulfonamide 1360614-48-7 C18H15N5O6S2 122 suppliers $14.00-$1792.00
Necrosulfonamide 1360614-48-7 C18H15N5O6S2 122 suppliers $14.00-$1792.00
Necrosulfonamide 1360614-48-7 C18H15N5O6S2 122 suppliers $14.00-$1792.00
Necrosulfonamide 1360614-48-7 C18H15N5O6S2 122 suppliers $14.00-$1792.00

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