Understanding selenium and glutathione as antiviral factors in COVID-19: Does the viral Mpro protease target host selenoproteins and glutathione synthesis?

Abstract

Glutathione peroxidases (GPX), a family of antioxidant selenoenzymes, functionally link selenium and glutathione, which both show correlations with clinical outcomes in COVID-19. Thus, it is highly significant that cytosolic GPX1 has been shown to interact with an inactive C145A mutant of Mpro, the main cysteine protease of SARS-CoV-2, but not with catalytically active wild-type Mpro. This seemingly anomalous result is what might be expected if GPX1 is a substrate for the active protease, leading to its fragmentation. We show that the GPX1 active site sequence is substantially similar to a known Mpro cleavage site, and is identified as a potential cysteine protease site by the Procleave algorithm. Proteolytic knockdown of GPX1 is highly consistent with previously documented effects of recombinant SARS-CoV Mpro in transfected cells, including increased reactive oxygen species and NF-kappaB activation. Because NF-kappaB in turn activates many pro-inflammatory cytokines, this mechanism could contribute to increased inflammation and cytokine storms observed in COVID-19. Using web-based protease cleavage site prediction tools, we show that Mpro may be targeting not only GPX1, but several other selenoproteins including SELENOF and thioredoxin reductase 1, as well as glutamate-cysteine ligase, the rate-limiting enzyme for glutathione synthesis. This hypothesized proteolytic knockdown of components of both the thioredoxin and glutaredoxin systems is consistent with a viral strategy to inhibit DNA synthesis, to increase the pool of ribonucleotides for RNA synthesis, thereby enhancing virion production. The resulting “collateral damage” of increased oxidative stress and inflammation would be exacerbated by dietary deficiencies of selenium, glutathione and glutathione precursors.

Selenium and selenoproteins in viral infection with potential relevance to COVID-19

“…In other cases (e.g. Zika virus, mumps virus and some pathogenic strains of avian influenza), there is no evidence of viral selenoprotein encoding, so the antisense interaction appears to serve some other function, for which the most obvious hypothesis involves the role of TXNRD in DNA synthesis [ 114 , 116 ]. Just as some large DNA viruses encode their own ribonucleotide reductase to increase DNA synthesis for virus production, some RNA viruses may attempt to boost RNA synthesis by inhibiting the diversion of ribonucleotides for DNA synthesis, for which thioredoxin serves as an electron donor for ribonucleotide reductase, which thus in turn requires TXNRD for sustained conversion of ribonucleotides to deoxyribonucleotides.…”

Long-COVID post-viral chronic fatigue syndrome and affective symptoms are associated with oxidative damage, lowered antioxidant defenses and inflammation: a proof of concept and mechanism study

“…Likewise, SARS-Cov-2 infection and acute COVID-19 are accompanied by an inflammatory response 29 , increased MPO activity 35 , indicants of oxidative damage 36–38 and increased NO production including increased levels of nitrotyrosine 39 , and lowered antioxidant defenses as indicated by reduced TAC levels 35, 39 , Gpx 40 and zinc 41 . Nevertheless, there are no data on whether the effects of the immune-inflammatory processes during acute infection, as indicated by lowered SpO2 and increased body temperature on the physio-affective phenome, are mediated by activated immune and O&NS (IO&NS) pathways.…”

The Status of Antioxidants and Oxidative Damage in Patients with COVID-19

“…They stated that disruption of GSH synthesis may be linked with a raise in clinical findings of COVID-19. 26 In our literature search, we could not find any studies that investigated the thiol/disulfide, GSH or GPx levels in patients with COVID-19. The data of this study showed that GSH was highly suppressed and GPx was elevated in the COVID-19 patients.…”