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Nitazoxanide, an antiviral thiazolide, depletes ATP-sensitive intracellular Ca(2+) stores

Omodele Ashiru1, Jonathon D Howe1, Terry D Butters1

  • 1Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, Oxfordshire OX1 3QU, UK.

Virology
|June 28, 2014
PubMed

Insights

Nitazoxanide (NTZ) depletes intracellular calcium stores, impacting viral replication. This mechanism underlies NTZ

Area of Science:

  • Virology
  • Cell Biology
  • Drug Discovery

Background:

  • Nitazoxanide (NTZ) is known to inhibit replication of several viruses.
  • Its effects on Flaviviridae family members, beyond Hepatitis C virus (HCV), are not well-defined.
  • Bovine viral diarrhoea virus (BVDV) serves as a surrogate model for HCV.

Purpose of the Study:

  • To investigate the effects of NTZ on BVDV replication.
  • To elucidate the molecular mechanisms underlying NTZ's antiviral activity.

Main Methods:

  • Treatment of cells with NTZ, with and without BVDV infection.
  • Measurement of PKR and eIF2α phosphorylation.
  • Assessment of intracellular calcium levels.
  • Analysis of ER stress markers and viral protein glycosylation/trafficking.

Main Results:

  • NTZ induced PKR and eIF2α phosphorylation in both uninfected and BVDV-infected cells.
  • NTZ treatment led to the depletion of ATP-sensitive intracellular calcium stores.
  • NTZ caused ER stress, altered viral protein N-linked glycosylation, and affected protein trafficking.
  • Cells adapted to ER stress by upregulating Ca(2+)-binding proteins like Bip and TCTP.

Conclusions:

  • Depletion of intracellular calcium stores is the primary consequence of NTZ treatment.
  • This calcium depletion is likely the key mechanism behind NTZ's antiviral effects against BVDV and potentially other viruses.
Keywords:
ER stressFlaviviridaeIntracellular Ca(2+)N-linked glycansPKRTCTP

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