Gasdermin E-derived caspase-3 inhibitors effectively protect mice from acute hepatic failure

Acta Pharmacol Sin. 2021 Jan;42(1):68-76. doi: 10.1038/s41401-020-0434-2. Epub 2020 May 26.

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.

Keywords: acute hepatic failure; apoptosis; caspase-3 inhibitor; gasdermin E; pyroptosis.

MeSH terms

  • Amino Acid Chloromethyl Ketones / chemistry
  • Amino Acid Chloromethyl Ketones / therapeutic use*
  • Animals
  • Apoptosis / drug effects
  • Bile Ducts / surgery
  • Caspase 3 / metabolism*
  • Caspase Inhibitors / chemistry
  • Caspase Inhibitors / therapeutic use*
  • Cell Line, Tumor
  • Humans
  • Ligation
  • Liver Diseases / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Docking Simulation
  • Oligopeptides / chemistry
  • Oligopeptides / therapeutic use*
  • Peptide Fragments / chemistry
  • Protective Agents / chemistry
  • Protective Agents / therapeutic use*
  • Pyroptosis / drug effects
  • Receptors, Estrogen / chemistry

Substances

  • Amino Acid Chloromethyl Ketones
  • Caspase Inhibitors
  • GSDME protein, human
  • Gsdme protein, mouse
  • Oligopeptides
  • Peptide Fragments
  • Protective Agents
  • Receptors, Estrogen
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Caspase 3