Abstract
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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Acknowledgements
This work was financially supported by the National Natural Science Foundation of China (HPH is supported by 81720108032, 81930109, and 81421005; and LJC is supported by 81973559), the Project for Major New Drug Innovation and Development (grants 2018ZX09711001-002-003 to HPH; 2018ZX09711002-001-004 to LJC), the Overseas Expertise Introduction Project for Discipline Innovation (G20582017001) to HPH, the “Double-First Class” initiative project (CPU2018GF09) and the Sanming Project of Medicine in Shenzhen (grants SZSM201801060 to HPH). We thank the Chinese Peptide Company for designing synthetic routes and performing compound synthesis in this study.
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LJC and HPH designed the study; WFX, QZ, CJD, HYS, YC, HH, YW, and JWW performed the experiments and collected and analyzed the data; LJC, HPH, and WFX wrote and revised the manuscript. WFX and QZ contributed equally to this work.
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Xu, Wf., Zhang, Q., Ding, Cj. et al. Gasdermin E-derived caspase-3 inhibitors effectively protect mice from acute hepatic failure. Acta Pharmacol Sin 42, 68–76 (2021). https://doi.org/10.1038/s41401-020-0434-2
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DOI: https://doi.org/10.1038/s41401-020-0434-2
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