Redox-Modulating Agents in the Treatment of Viral Infections

Abstract

Viruses use cell machinery to replicate their genome and produce viral proteins. For this reason, several intracellular factors, including the redox state, might directly or indirectly affect the progression and outcome of viral infection. In physiological conditions, the redox balance between oxidant and antioxidant species is maintained by enzymatic and non-enzymatic systems, and it finely regulates several cell functions. Different viruses break this equilibrium and induce an oxidative stress that in turn facilitates specific steps of the virus lifecycle and activates an inflammatory response. In this context, many studies highlighted the importance of redox-sensitive pathways as novel cell-based targets for therapies aimed at blocking both viral replication and virus-induced inflammation. In the review, we discuss the most recent findings in this field. In particular, we describe the effects of natural or synthetic redox-modulating molecules in inhibiting DNA or RNA virus replication as well as inflammatory pathways. The importance of the antioxidant transcription factor Nrf2 is also discussed. Most of the data reported here are on influenza virus infection. We believe that this approach could be usefully applied to fight other acute respiratory viral infections characterized by a strong inflammatory response, like COVID-19.

The Role of Glutathione in Protecting against the Severe Inflammatory Response Triggered by COVID-19

“…During viral infections, an intracellular GSH depletion is mediated by multiple mechanisms and is crucial for viral replication [99]. Although several in vitro and in vivo studies demonstrate that the administration of GSH inhibits viral replication, to date very few clinical trials support the pharmacological use of NAC in respiratory viral infection in vivo (reviewed in [100]). GSH treatment is a promising approach, but high doses of GSH are necessary to achieve a therapeutic efficacy, due to its poor transport into the cells and tissues.…”

“…GSH treatment is a promising approach, but high doses of GSH are necessary to achieve a therapeutic efficacy, due to its poor transport into the cells and tissues. GSH delivery could be improved by some derivatives with hydrophobic chains of different length or by I-152, which is a conjugate of NAC and s-acetyl-β-mercaptoethylamine (MEA), which is able to release NAC and MEA and increase GSH content [100].…”

Glutathione Supplementation as an Adjunctive Therapy in COVID-19

“…Influenza viruses induce oxidative stress mediated by excess of reactive oxygen species (ROS) and a decrease of reduced GSH the main intracellular antioxidant, and that such conditions favor viral replication [ 95 , 96 , 97 , 98 ]. The production of ROS is mediated by the activity of the NOX family, which consists of seven members: NOX1 to NOX5 and the two dual oxidases, Duox1 and Duox2, expressed in most cell types [ 99 ].…”

Perspectives on mechanistic implications of ROS inducers for targeting viral infections

“…Hence, the administration of antioxidants like Vitamin C, which has been proved to be preventive against viral pneumonia, can serve as an ideal prevention strategy against viral infections; however, ROS induction can be superlative in disease therapy ( Hemilä and Louhiala, 2013 ; Kim et al, 2013 ). Further, there are several host redox and other associated genes which are modulated during a viral infection enabling the viral propagation and pathogenesis as depicted in Table 1 (( Ahmed and Rahman, 2006 ; Bender and Hildt, 2019 ; Bottino-Rojas et al, 2018 ; Checconi et al, 2020 ; Chen et al, 2020a ; Cuadrado et al, 2020 ; Jacoby and Choi, 1994 ; Lee, 2018a ; Simenauer et al, 2019 ; Zhang et al, 2020 ).…”

“… S. No. Redox and other associated genes activated during RNA viral infections Reference 1 Superoxide dismutase 3 (SOD3) ( Ahmed and Rahman, 2006 ) 2 Activating transcription factor 4 (ATF4) 3 Metallothionein 2A (M2TA) 4 Nuclear factor erythroid 2-related factor 2 (NRF-2) ( Bottino-Rojas et al, 2018 ; McCord et al, 2020) 5 Heme oxygenase (HMOX1) ( Cuadrado et al, 2020 ; Singh et al, 2018 ) 6 Sulfiredoxin-1 (SRXN-1) ( Simenauer et al, 2019 ) 7 NADPH quinone dehydrogenase 1 (NQO1) 8 Glutamate cysteine ligase catalytic and regulatory subunits (GCLC and GCLM) ( Lee, 2018a ) 9 Glutathione S-transferase (GST) 10 Uridine diphosphate glucuronosyltransferase (UDPGT) 11 Catalase (CAT) 12 Glucose 6 phosphate dehydrogenase (G6PD) 13 Glutathione peroxidase-1 (GPx) 14 Glutathione disulfide reductase (GSR) Checconi et al (2020) 15 Copper/zinc superoxide dismutase (Cu/ZnSOD) ( Jacoby and Choi, 1994 ) 16 Manganese superoxide dismutase (MnSOD) 17 Indole- amine dioxygenase (IDO) 18 Mel...…”