The anti-hepatitis C agent nitazoxanide induces phosphorylation of eukaryotic initiation factor 2alpha via protein

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Studying RNA Interactors of Protein Kinase RNA-Activated during the Mammalian Cell Cycle
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Studying RNA Interactors of Protein Kinase RNA-Activated during the Mammalian Cell Cycle

Published on: March 5, 2019

Menashe Elazar1, Michael Liu, Sean A McKenna

  • 1Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA.

Gastroenterology
|August 12, 2009
PubMed
Abstract

Insights

Nitazoxanide (NTZ) activates protein kinase R (PKR), enhancing the host cell's antiviral defenses against hepatitis C virus (HCV). This mechanism explains NTZ's clinical efficacy and potential to boost interferon's antiviral effects.

Area of Science:

  • Virology
  • Immunology
  • Pharmacology

Background:

  • Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease globally, necessitating novel therapeutic strategies.
  • Nitazoxanide (NTZ), an antiparasitic drug, has demonstrated antiviral activity against HCV, with potential to augment interferon (IFN) therapy.
  • The molecular mechanisms underlying NTZ's antiviral effects, particularly its interaction with host cell antiviral pathways, remained largely unknown.

Purpose of the Study:

  • To investigate the molecular basis of Nitazoxanide's (NTZ) antiviral activity against Hepatitis C Virus (HCV).
  • To elucidate the role of eukaryotic initiation factor-2alpha (eIF2alpha) phosphorylation and its regulatory kinase, protein kinase activated by double-stranded RNA (PKR), in NTZ's mechanism of action.
  • To determine if NTZ modulates PKR activation and its downstream effects on cellular antiviral responses.

Main Methods:

  • Analysis of NTZ's effects on eIF2alpha and PKR phosphorylation in cells supporting HCV RNA replication.
  • In vitro biochemical assays to assess NTZ's impact on PKR autophosphorylation and kinase activity.
  • Evaluation of NTZ-induced eIF2alpha phosphorylation in the presence of PKR-specific inhibitors.

Main Results:

  • NTZ treatment significantly increased eIF2alpha phosphorylation, a key host antiviral defense mechanism.
  • Co-administration of IFN enhanced NTZ-induced eIF2alpha phosphorylation.
  • NTZ promoted PKR autophosphorylation and increased its kinase activity, which was essential for eIF2alpha phosphorylation.
  • Inhibition of PKR autophosphorylation reduced NTZ-induced eIF2alpha phosphorylation, confirming PKR's central role.

Conclusions:

  • NTZ activates protein kinase R (PKR), a critical component of the innate antiviral immune response.
  • PKR activation by NTZ is a key mechanism contributing to its antiviral effects against HCV.
  • NTZ represents a potential new therapeutic agent that can potentiate and mimic interferon's antiviral actions.

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