上睑下垂
细胞凋亡
程序性细胞死亡
效应器
半胱氨酸蛋白酶
半胱氨酸蛋白酶3
坏死
癌症研究
药理学
医学
生物
细胞生物学
内科学
生物化学
作者
Wanfeng Xu,Quan Zhang,Chujie Ding,Huiyong Sun,Yuan Che,Hai Huang,Yun Wang,Jiawei Wu,Haiping Hao,Lijuan Cao
标识
DOI:10.1038/s41401-020-0434-2
摘要
Programmed cell death (PCD), including apoptosis, apoptotic necrosis, and pyroptosis, is involved in various organ dysfunction syndromes. Recent studies have revealed that a substrate of caspase-3, gasdermin E (GSDME), functions as an effector for pyroptosis; however, few inhibitors have been reported to prevent pyroptosis mediated by GSDME. Here, we developed a class of GSDME-derived inhibitors containing the core structure of DMPD or DMLD. Ac-DMPD-CMK and Ac-DMLD-CMK could directly bind to the catalytic domains of caspase-3 and specifically inhibit caspase-3 activity, exhibiting a lower IC50 than that of Z-DEVD-FMK. Functionally, Ac-DMPD/DMLD-CMK substantially inhibited both GSDME and PARP cleavage by caspase-3, preventing apoptotic and pyroptotic events in hepatocytes and macrophages. Furthermore, in a mouse model of bile duct ligation that mimics intrahepatic cholestasis-related acute hepatic failure, Ac-DMPD/DMLD-CMK significantly alleviated liver injury. Together, this study not only identified two specific inhibitors of caspase-3 for investigating PCD but also, more importantly, shed light on novel lead compounds for treating liver failure and organ dysfunctions caused by PCD.
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