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. © 2011 Mary Ann Liebert, Inc.

Redox regulation of the influenza hemagglutinin maturation process: a new cell-mediated strategy for anti-influenza therapy / Rossella, Sgarbanti; Nencioni, Lucia; Amatore, Donatella; Coluccio, Paolo; Alessandra, Fraternale; Patrizio, Sale; Mammola, CATERINA LOREDANA; Guido, Carpino; Gaudio, Eugenio; Mauro, Magnani; Maria R., Ciriolo; Enrico, Garaci; Palamara, ANNA TERESA. - In: ANTIOXIDANTS & REDOX SIGNALING. - ISSN 1523-0864. - 15:3(2011), pp. 593-606. [10.1089/ars.2010.3512]

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

NENCIONI, Lucia;AMATORE, DONATELLA;COLUCCIO, PAOLO;MAMMOLA, CATERINA LOREDANA;Guido Carpino;GAUDIO, EUGENIO;PALAMARA, ANNA TERESA
2011

Abstract

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. © 2011 Mary Ann Liebert, Inc.
2011
01 Pubblicazione su rivista::01a Articolo in rivista
Redox regulation of the influenza hemagglutinin maturation process: a new cell-mediated strategy for anti-influenza therapy / Rossella, Sgarbanti; Nencioni, Lucia; Amatore, Donatella; Coluccio, Paolo; Alessandra, Fraternale; Patrizio, Sale; Mammola, CATERINA LOREDANA; Guido, Carpino; Gaudio, Eugenio; Mauro, Magnani; Maria R., Ciriolo; Enrico, Garaci; Palamara, ANNA TERESA. - In: ANTIOXIDANTS & REDOX SIGNALING. - ISSN 1523-0864. - 15:3(2011), pp. 593-606. [10.1089/ars.2010.3512]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/12867
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