Abstract
Host-directed therapy using drugs that target cellular pathways required for virus lifecycle or its clearance might represent an effective approach for treating infectious diseases. Changes in redox homeostasis, including intracellular glutathione (GSH) depletion, are one of the key events that favor virus replication and contribute to the pathogenesis of virus-induced disease. Redox homeostasis has an important role in maintaining an appropriate Th1/Th2 balance, which is necessary to mount an effective immune response against viral infection and to avoid excessive inflammatory responses. It is known that excessive production of reactive oxygen species (ROS) induced by viral infection activates nuclear factor (NF)-kB, which orchestrates the expression of viral and host genes involved in the viral replication and inflammatory response. Moreover, redox-regulated protein disulfide isomerase (PDI) chaperones have an essential role in catalyzing formation of disulfide bonds in viral proteins. This review aims at describing the role of GSH in modulating redox sensitive pathways, in particular that mediated by NF-kB, and PDI activity. The second part of the review discusses the effectiveness of GSH-boosting molecules as broad-spectrum antivirals acting in a multifaceted way that includes the modulation of immune and inflammatory responses.
Highlights
Most antiviral drugs target specific steps of the viral replicative cycle, i.e., adsorption and entry into the cells, reverse transcription, viral DNA polymerization as well as viral release and comprise inhibitors of viral entry, viral polymerase and viral proteases [1]
The association of the envelope (E) protein with the S protein may be mediated by the formation of disulfide bonds between the corresponding cysteines residues [99]. These findings suggest that redox state may influence both folding/maturation of single proteins as well as later assembly in coronavirus life cycle
In vitro studies aimed at elucidating the molecular mechanisms through which I-152 and C4-GSH could exert the effects observed in vivo showed that: 2h pretreatment with high dose of I-152 in peritoneal LPS/IFN-γ-stimulated macrophages blocked nuclear factor (NF)-kB nuclear translocation and prolonged signal transducer and activator of transcription (STAT)-1/ Interferon regulatory factor (IRF)-1 signaling pathway; 2h pretreatment with high dose of C4-GSH in the same experimental model favored NF-kB signaling likely by maintaining in a reduced state the highly conserved cysteine residue in the N-terminal region of the Rel homology domain [155]
Summary
Most antiviral drugs target specific steps of the viral replicative cycle, i.e., adsorption and entry into the cells, reverse transcription (retroviruses), viral DNA polymerization as well as viral release and comprise inhibitors of viral entry, viral polymerase and viral proteases [1]. In particular IL-6, have been described to be responsible for lung damage, inducing vascular endothelial growth factor (VEGF) expression in epithelial cells and increasing vessel permeability in SARS as well as for lethal complications of COVID19 [80] For this reason, therapies targeting the host immune system may be effective for COVID-19; in particular, IL-6 blockade, e.g., by inhibiting NF-kB signaling, seems to be the most promising strategy [80]. In the ER of virus-infected cells the sustained production of viral proteins overloads the processing systems interfering with the folding of host proteins, leading to an increased burden of ER/Golgi trafficking This condition induces ER stress and the subsequent activation of the unfolded protein response (UPR), a conserved cellular pathway that modulates translation, membrane biosynthesis, and the levels of ER chaperones. It was synthesized with the aim to design a new potent lipophilic antioxidant molecule with improved delivery properties of the two compounds
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