Redox regulation of the influenza hemagglutinin maturation process: a new cell-mediated strategy for anti-influenza therapy

Antioxid Redox Signal. 2011 Aug 1;15(3):593-606. doi: 10.1089/ars.2010.3512. Epub 2011 May 19.


Aim: The aim of this study was to determine whether GSH-C4, a hydrophobic glutathione derivative, affects in vitro and in vivo influenza virus infection by interfering with redox-sensitive intracellular pathways involved in the maturation of viral hemagglutinin (HA).

Results: GSH-C4 strongly inhibited influenza A virus replication in cultured cells and in lethally infected mice, where it also reduced lung damage and mortality. In cell-culture studies, GSH-C4 arrested viral HA folding; the disulfide-rich glycoprotein remained in the endoplasmic reticulum as a reduced monomer instead of undergoing oligomerization and cell plasma-membrane insertion. HA maturation depends on the host-cell oxidoreductase, protein disulfide isomerase (PDI), whose activity in infected cells is probably facilitated by virus-induced glutathione depletion. By correcting this deficit, GSH-C4 increased levels of reduced PDI and inhibited essential disulfide bond formation in HA. Host-cell glycoprotein expression in uninfected cells was unaffected by glutathione, which thus appears to act exclusively on glutathione-depleted cells.

Innovation: All currently approved anti-influenza drugs target essential viral structures, and their efficacy is limited by toxicity and by the almost inevitable selection of drug-resistant viral mutants. GSH-C4 inhibits influenza virus replication by modulating redox-sensitive pathways in infected cells, without producing toxicity in uninfected cells or animals. Novel anti-influenza drugs that target intracellular pathways essential for viral replication ("cell-based approach") offer two important potential advantages: they are more difficult for the virus to adapt to and their efficacy should not be dependent on virus type, strain, or antigenic properties.

Conclusion: Redox-sensitive host-cell pathways exploited for viral replication are promising targets for effective anti-influenza strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Disease Models, Animal
  • Disulfides / chemistry
  • Dogs
  • Female
  • Glutathione / analogs & derivatives*
  • Hemagglutinins, Viral / metabolism*
  • Influenza A virus / drug effects*
  • Mice
  • Mice, Inbred BALB C
  • Orthomyxoviridae Infections / drug therapy*
  • Orthomyxoviridae Infections / metabolism
  • Oxidation-Reduction
  • Protein Disulfide-Isomerases / metabolism
  • Protein Folding / drug effects
  • Virus Replication / drug effects


  • Disulfides
  • Hemagglutinins, Viral
  • glutathione-C4
  • Protein Disulfide-Isomerases
  • Glutathione