Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19)

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Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19)

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Chemistry of Quercetin

Abstract

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) represents an emergent global threat which is straining worldwide healthcare capacity. As of May 27th, the disease caused by SARS-CoV-2 (COVID-19) has resulted in more than 340,000 deaths worldwide, with 100,000 deaths in the US alone. It is imperative to study and develop pharmacological treatments suitable for the prevention and treatment of COVID-19. Ascorbic acid is a crucial vitamin necessary for the correct functioning of the immune system. It plays a role in stress response and has shown promising results when administered to the critically ill. Quercetin is a well-known flavonoid whose antiviral properties have been investigated in numerous studies. There is evidence that vitamin C and quercetin co-administration exerts a synergistic antiviral action due to overlapping antiviral and immunomodulatory properties and the capacity of ascorbate to recycle quercetin, increasing its efficacy. Safe, cheap interventions which have a sound biological rationale should be prioritized for experimental use in the current context of a global health pandemic. We present the current evidence for the use of vitamin C and quercetin both for prophylaxis in high-risk populations and for the treatment of COVID-19 patients as an adjunct to promising pharmacological agents such as Remdesivir or convalescent plasma.

Keywords: SARS-Cov-2, COVID-19, vitamin C, quercetin, flavonoids, antiviral,

Introduction

It is serendipitous (or perhaps indicative of hard work) that the Nobel prize winner Szent-Gyorgyi discovered both ascorbic acid (vitamin C) and the flavonoid quercetin (at the time labeled vitamin P) (). Ascorbic acid is an essential vitamin with known antiviral properties () which is under investigation for its beneficial effects during the stress response in sepsis and critically ill patients ().

Vitamin C exerts its antiviral properties by supporting lymphocyte activity, increasing interferon-α production, modulating cytokines, reducing inflammation, improving endothelial dysfunction, and restoring mitochondrial function (). There are also suggestions that vitamin C may be directly viricidal (). These in vitro effects, as we previously discussed (), constitute a reflection of both the supra-physiological concentrations of ascorbate and the interaction between vitamin C and metal-containing culture media—both of which are pro-oxidant, generating reactive oxygen species.

Quercetin (also known as 3,3′,4′5,7-pentahydroxyflavone) is a widely distributed plant flavonoid, found in several vegetables, leaves, seeds, and grains, where it is conjugated with residual sugars to form quercetin glycosides (). Studies suggest that quercetin supplementation may promote antioxidant (), anti-inflammatory, antiviral (), and immunoprotective effects (). Quercetin has been studied in various types and models of viral infection due to its promising antiviral effects in inhibiting polymerases (), proteases (), reverse transcriptase (), suppressing DNA gyrase, and binding viral capsid proteins (, ).

In this review we collate the evidence of the antiviral properties of quercetin, describe its biologic action and pharmacokinetics profile, expand on our previous review of vitamin C, discuss their synergistic actions, and propose this experimental multi-drug approach for the prevention and treatment of SARS-CoV-2/COVID-19 pandemic.

Discussion

A multi-drug approach with quercetin and vitamin C may disrupt virus entry, replication, enzyme activity and assembly, and concurrently fortify the immune response promoting early IFNs production, modulating interleukins, promoting T cell maturation, and phagocytic activity. Quercetin and ascorbic acid co-administration represents an experimental strategy for prophylaxis and treatment of several respiratory viruses, such as SARS-CoV-2. The blockage of virus entry represents a key strategy and quercetin impedes viral membrane fusion for both influenza and SARS-Cov in vitro (). Quercetin also targets viral polymerases and may disrupt replication via the inhibition of reverse transcriptase enzymes. Quercetin further inhibits SARS 3CL protease by binding to its GLN189 site (), which is expressed similarly by SARS-COV-2 () and provides a direct mechanistic rationale for its experimental clinical use—in addition to its immunoenhancing and anti-inflammatory actions. Despite the limitations of in vitro research, it is noteworthy that the few in vivo models reviewed here indicate increased survival from lethal viral infection when treated with quercetin (, ). Some studies suggest that oral administration and metabolic processing (methylation, conjugation, etc.) is necessary, and have identified quercetin derivates, which display variable Tmax, as responsible for a cooperative antiviral activity ().

Vitamin C exerts immunomodulatory activity, enhancing interferon production through STAT3 phosphorylation (), limiting cytokine-induced organ damage (), promoting survival in lethal infections () and, importantly, is able to recycle oxidized quercetin (), enhancing its antiviral effects. SARS-Cov-2 virus infection may initiate a strong inflammatory and dysregulated reaction in the lung with increased levels of IL-6 and a “cytokine-storm” () which has been shown to provoke either an asymptomatic, mild, or severe infections This cytokine dysregulation may be associated with neutrophil extracellular traps () and alterations in T cell activity (). These immunological alterations which have characterized our current understanding of Covid-19 suggest that agents which target immune modulation, rather than direct viricidal activity, may present exciting targets for pharmacological intervention. In this scenario, Vitamin C and quercetin co-administration may represent a safe, effective, and inexpensive antiviral and immunomodulative approach for both the prophylaxis of high-risk populations and the treatment of both mild and severe cases.

They have also consistently been shown to display excellent safety profiles, and a consideration of risks and benefits in their therapeutic potential should be placed within this context. Vitamin C is a widely available supplement which many millions of people use already, and we have highlighted its antiviral properties in conjunction with quercetin. Due to its large-scale use, vitamin C in particular would be a cheap intervention with which to ascertain these compounds' efficacy as a prophylactic intervention. The prophylactic use of over-the-counter vitamin supplementation to combat infection is a behavior many people engage with already. Research into the potential prophylactic administration of vitamin C and quercetin in high-risk groups is therefore warranted.

The excellent side effect profile of these agents would also suggest that they may complement interventions which have displayed potential benefits in treating Covid-19, such as Remdesivir () and convalescent plasma (, ), which we believe warrants their experimental use in clinical trials.

There are potential limitations of their use in clinical studies. Both agents are present in varying degrees in individuals' diets and global recommendations for vitamin C intake vary extensively across the globe (). Prophylactic interventions in general populations within the community will therefore be confounded by the quantity present in differing diets. Agents such as vitamin C also have well-characterized beneficial effects apart from the antiviral properties we have highlighted here. Supplementation with these agents may therefore promote general health and indirectly affect the capacity of individuals to combat viral infection. Although this would diminish the ability to identify the direct antiviral properties of vitamin C in clinical studies it may have ancillary benefits of promoting general health, which may be particularly pertinent if administered in communities with greater deprivation or from less economically developed countries.

Conclusion

Quercetin displays a broad range of antiviral properties which can interfere at multiple steps of pathogen virulence -virus entry, virus replication, protein assembly- and that these therapeutic effects can be augmented by the co-administration of vitamin C. Furthermore, due to their lack of severe side effects and low-costs, we strongly suggest the combined administration of these two compounds for both the prophylaxis and the early treatment of respiratory tract infections, especially including COVID-19 patients.

To read the full article:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318306/?fbclid=IwAR2IhbxHtz3sj7DSknvA8JaHJXUnl3ohygYRrky85qQCB_frxvSB9t4ybuw

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