San Raffaele Pisana Scientific Institute for Research, Hospitalization, and Health Care, Rome, Italy.
Antioxid Redox Signal. 2011 Aug 1;15(3):593-606. doi: 10.1089/ars.2010.3512. Epub 2011 May 19.
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).
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.
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.
Redox-sensitive host-cell pathways exploited for viral replication are promising targets for effective anti-influenza strategies.
本研究旨在通过干扰参与病毒血凝素 (HA) 成熟的氧化还原敏感细胞内途径，确定疏水性谷胱甘肽衍生物 GSH-C4 是否影响体外和体内流感病毒感染。
GSH-C4 强烈抑制培养细胞中的甲型流感病毒复制，并在致死性感染的小鼠中也降低了肺损伤和死亡率。在细胞培养研究中，GSH-C4 阻断了病毒 HA 的折叠；富含二硫键的糖蛋白作为还原的单体仍留在内质网中，而不是进行寡聚化和细胞质膜插入。HA 的成熟依赖于宿主细胞氧化还原酶，即蛋白二硫键异构酶 (PDI)，其在感染细胞中的活性可能是由病毒诱导的谷胱甘肽耗竭所促进的。通过纠正这种缺陷，GSH-C4 增加了还原型 PDI 的水平，并抑制了 HA 中必需的二硫键形成。谷胱甘肽对未感染细胞中的宿主细胞糖蛋白表达没有影响，因此谷胱甘肽似乎仅作用于谷胱甘肽耗竭的细胞。
所有目前批准的抗流感药物都针对病毒的必需结构，其疗效受到毒性和几乎不可避免的选择耐药病毒突变体的限制。GSH-C4 通过调节感染细胞中的氧化还原敏感途径来抑制流感病毒复制，而在未感染的细胞或动物中不产生毒性。针对病毒复制必需的细胞内途径的新型抗流感药物具有两个重要的潜在优势：它们更难被病毒适应，并且其疗效不应依赖于病毒类型、株系或抗原特性。
用于病毒复制的氧化还原敏感宿主细胞途径是有效的抗流感策略的有前途的靶点。
