Resveratrol _Speculation_ on_(COVID-19) Updated with link to early computer informatics finding.

Finding: Resveratrol may be active against COVID-19 according to the EpiMed software program. This is an update on my previous post on resveratrol, a nutritional supplement, in the context of COVID-19.

I also copy the abstracts of two previous articles investigating a number of substances including resveratrol against both MERS and SARS. This is speculative. Don't take this as any kind of statement that it is in any way a treatment.

In a previous post I explained how resveratrol - which displayed activity against a similar betacoronavirus, "MERS" and (two related compounds were synthesized and found to be useful against SARS.)

Resveratrol is a uniquely helpful substance in medicine whose properties are widely investigated in research as promising candidates for functional foods. Resveratrol is one of a great many substances invented over a long iterative process by plants. It seems to have helped at least one plant, the Metasequoia or "dawn redwood", survive essentially unchanged for 150 million years.

That's a very long time. It's a living fossil.

However, it's definitely true that despite what the US drug industry would have us think, phytochemicals are in many ways on the cutting edge of medicine.

The second paper reviewed seems focused on these newly syntjesized analogs of resveratrol (patentable) and not resveratrol itself. When structure activity relationships of a group of substances are investigated they can vary quite a bit.

Here the language is ambiguous on SARS itself. My conclusion for multiple reasons is that it seems it is likely worth looking at for COVID-19 regardless of whether it was resveratrol or its close analog that was found to be active. I think that pinosilvin is also active against SARS.

Whether it would reduce mortality is still totally unknown. But its properties seem to dovetail well with the complex problems COVID-19 causes, its clear.

In this post I am going to look a bit more closely at the two previous studies. Also here is a link to the software article.

Speculate what might be possible if it works in inhibiting the morbidity of COVID-19. I propose that as it is a food, if it's beneficial, that should be taken advantage of by using it in a functional food.

Resveratrol works best buccally (absorbed into the mucus membranes of the mouth) But GI COVID-19 might benefit greatly by putting it into some form where it would better disseminate throughout the GI tract.

I propose that it be used in lozenges. Suppose it is made into a throat lozenge form. Possibly with glutamine which also improves gut barrier function.

L-Glutamine might assist in slowing the dissolution rate of lozenges made with a hard candy material. (Just speculating)

It might provide hours of relief against a virus.

Another way that might be helpful is mixing it into a carbonated drink (which makes them foam up) and drinking it rapidly.

The many beneficial attributes of resveratrol as it might be applied to the COVID-19 virus were enumerated in the previous article.

Even an incomplete suppression of the COVID-19 infection would save a great many lives right now.

50% trans resveratrol powder is available at low cost and is quite safe to take generally. As it also is anticandidicidal, (patients in ICUs have a serious problem with candida also) I can see it being used with many benefits in the ICU.

Cosmetically, though it has a problem, it looks like dirt. Also, taken buccally as I describe it can and will stain the teeth, requiring much more frequent tooth brushing.

In a paper in BMC Infectious Diseases, one of the Nature family of medical journals "Effective inhibition of MERS-CoV infection by resveratrol" was described. [1]

-----------------------------------------

UPDATE: Yesterday a Chinese journal published an article [link to English abstract] within which a medical informatics program identified resveratrol as a possible candidate for study particularly for COVID-19 caused heart damage. Note they still need validation, this is a fairly early result.

" The drugs predicted by EpiMed's apparent precision treatment prediction platform for disease-drug association analysis are mainly TNF-α inhibitors, resveratrol, ritonavir, paeony, retinoic acid, forsythia, and houttuynia cordata. Conclusions: The abnormal activation of multiple inflammatory pathways may be the cause of heart failure in patients after coronavirus infection. Resveratrol, ritonavir, retinoic acid, amaranth, forsythia, houttuynia may have therapeutic effects. Future basic and clinical research is warranted to validate present results and hypothesis"

Here are the Journal titles, abstracts, authors and links

[1]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5307780/

BMC Infect Dis. 2017; 17: 144.
Published online 2017 Feb 13. doi: 10.1186/s12879-017-2253-8


PMCID: PMC5307780
PMID: 28193191
Effective inhibition of MERS-CoV infection by resveratrol

AUTHORS:
Shih-Chao Lin, Chi-Tang Ho, Wen-Ho Chuo, Shiming Li, Tony T. Wang, corresponding author  tony.wang@sri.com, Chi-Chen Lin

Abstract


Background
Middle East Respiratory Syndrome coronavirus (MERS-CoV) is an emerging viral pathogen that causes severe morbidity and mortality. Up to date, there is no approved or licensed vaccine or antiviral medicines can be used to treat MERS-CoV-infected patients. Here, we analyzed the antiviral activities of resveratrol, a natural compound found in grape seeds and skin and in red wine, against MERS-CoV infection.

Methods
We performed MTT and neutral red uptake assays to assess the survival rates of MERS-infected Vero E6 cells. In addition, quantitative PCR, western blotting, and immunofluorescent assays determined the intracellular viral RNA and protein expression. For viral productivity, we utilized plaque assays to confirm the antiviral properties of resveratrol against MERS-CoV.

Results
Resveratrol significantly inhibited MERS-CoV infection and prolonged cellular survival after virus infection. We also found that the expression of nucleocapsid (N) protein essential for MERS-CoV replication was decreased after resveratrol treatment. Furthermore, resveratrol down-regulated the apoptosis induced by MERS-CoV in vitro. By consecutive administration of resveratrol, we were able to reduce the concentration of resveratrol while achieving inhibitory effectiveness against MERS-CoV.

Conclusion
In this study, we first demonstrated that resveratrol is a potent anti-MERS agent in vitro. We perceive that resveratrol can be a potential antiviral agent against MERS-CoV infection in the near future.

Keywords:
MERS-CoV, Middle East Respiratory Syndrome Virus, Resveratrol, MERS-CoV virus infection, Inhibition

Go to:


Background
Middle East Respiratory Syndrome (MERS) is a viral respiratory illness caused by a novel coronavirus (MERS-CoV) which was identified in Saudi Arabia in 2012 [1, 2]. Up to December 2016, the mortality rate of MERS patients is 35.4% with 652 deaths out of 1842 confirmed cases [3]. There is still no effective anti-MERS medicine or vaccine commercially available in the market. One previous study showed that stilbene derivatives could contain antiviral activities against Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) [4]. As a result, we tested whether a natural stilbene derivative, resveratrol (trans-3, 5, 4′-trihydroxystilbene) inhibits the MERS-CoV infection in this study. Resveratrol exists widely in different plants, including grape (Vitis vinifera), Huzhang (Polygonum cuspidatum) and cranberry (Vaccinium macrocarpon)[5].

In the past, resveratrol was demonstrated to decrease the production of nitric oxide in tissue, and thereby reduce inflammation [6–8]. Resveratrol also acts as an antioxidant to remove free radicals [9, 10], thus restrains tumor growth [11] and even age-related diseases [12, 13]. Resveratrol also inhibits STAT3 signaling pathway [14], the mTOR signaling [15], and the hedgehog signaling pathway [16]. Furthermore, resveratrol reportedly constrains infections caused by multiple pathogens, such as Helicobacter pylori [17], Staphylococcus aureus [18] or Toxoplasma gondii [19]. Interestingly, resveratrol has been demonstrated to exert antiviral effects against various viral infections, including Epstein-Barr virus (EBV) [20, 21], enterovirus 71 (EV71) [22], and herpes simplex virus (HSV) [23], as well as respiratory viral infections caused by influenza [24], respiratory syncytial virus (RSV) [25, 26], and rhinovirus [27]. However, it remains unknown whether resveratrol can inhibit MERS-CoV infection. In this study, we evaluated the antiviral effectiveness of resveratrol against MERS-CoV with an in vitro model.

-------------------------------------------

[2]

https://www.sciencedirect.com/science/article/pii/S0223523406001437?via%3Dihub


Eur J Med Chem. 2006 Sep;41(9):1084-9. Epub 2006 Jul 27.
Synthesis of stilbene derivatives with inhibition of SARS coronavirus replication.
Li YQ1, Li ZL, Zhao WJ, Wen RX, Meng QW, Zeng Y.


Author information
1
State Key Laboratory of Fine Chemicals, Dalian University of Technology, 158 Zhongshan Road, BOX 90, Dalian, Liaoning Province 116012, China.


Abstract
Stilbene derivatives have wide range of activities. In an effort to find other potential activities of this kind of compounds, 17 derivatives, including resveratrol, were synthesized. Twelve of them were evaluated for their antiviral potential against severe acute respiratory syndrome (SARS)-CoV-induced cytopathicity in Vero E6 cell culture. The result showed that SARS virus was totally inhibited by compounds 17 and 19 (<or=0.5 mg ml(-1)) and no significant cytotoxic effects were observed in vitro.

PMID: 16875760 DOI: 10.1016/j.ejmech.2006.03.024

1. Introduction
Stilbene derivatives are widely distributed in nature, which are thought to be phytoalexins. There is a growing interest in stilbene derivatives because many activities have been observed in some of the naturally occurring as well as some of the synthetic stilbenes. Activities include antimicrobial [1], [2], [3], antioxidant [4], [5], antileukemic [6], anti-platelet aggregative [7], [8], protein tyrosine kinase inhibitory [9], anti-inflammatory [10], [11], anticarcinogenic activity [12], [13], anti-HIV [14], [15] and anti-herpes simplex virus [16]. In the course of our research for potential activities of stilbene derivatives, we designed different hydroxyl substituted sites against resveratrol and kept the trans structure to simulate this kind of phytoalexins.

In early 2003, severe acute respiratory syndrome (SARS) broke out in China and other countries. Many scholars and researchers were engaged in the search of anti-SARS agents and vaccines. At the same time, we also used this kind of compounds to the urgent antiviral filtration in vitro. The result was exciting that the change of hydroxyl group's site and the introduction of nitrogen atom were beneficial to the anti-SARS activity. Especially the substituted sites of hydroxyl groups in compounds 17 and 19 have been demonstrated to be a key structure element of anti-SARS virus.

No one knows the likelihood of evolution of SARS-CoV in human and animals. Moreover the complete understanding of pathogenesis of SARS remains tentative. In this study, we evaluated such stilbene derivatives for their potential to inhibit SARS-CoV replication for the first time and thought this discovery would be beneficial to the anti-SARS-CoV development.

-----------------------------------------------