• Rossella Sgarbanti, Lucia Nencioni, Donatella Amatore, Paolo Coluccio, Alessandra Fraternale, Patrizio Sale, Caterina L Mammola, Guido Carpino, Eugenio Gaudio, Mauro Magnani, Maria R Ciriolo, Enrico Garaci, and Anna Teresa Palamara.
• San Raffaele Pisana Scientific Institute for Research, Hospitalization, and Health Care, Rome, Italy.
• Antioxid. Redox Signal. 2011 Aug 1;15(3):593-606.

AimThe 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).ResultsGSH-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.InnovationAll 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.ConclusionRedox-sensitive host-cell pathways exploited for viral replication are promising targets for effective anti-influenza strategies.

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