Disclaimer: This article is not intended as medical advice. The author does NOT claim that any of the inhibitors discussed in this article are effective as treatments or cures of Covid-19, nor of any other disease or condition. More research is needed, especially clinical studies. Current research on this topic is very preliminary.

Introduction

In a preprint article posted June 29, 2020, a group of researchers from the Chinese Academy of Sciences (Xia et al. 2020) presented their theory that a single structural protein from SARS-CoV-2, the E-channel, is sufficient by itself to cause the cytokine storm, which is responsible for so many Covid-19 patient deaths. They also proposed certain E-channel inhibitors, which might protect against this damage by binding to the E-channel. However, those inhibitors are not readily available. They are neither FDA-approved, nor available over-the-counter.

Another issue is whether the inhibition of E-channel would be a sufficient intervention, once a cytokine storm begins. The most suitable role for an inhibitor, then, is in advance of a cytokine storm and also in advance of any severe symptoms. An E-channel inhibitor might be given to patients from the beginning of diagnosis, so as to prevent the immune system from spinning out of control. But such a role requires a medication with side effects that are mild or rare. For these reasons, I focused my search for E-channel inhibitors mainly on natural compounds available over-the-counter and on widely-used medications with very limited side effects and contraindications

I performed a search of molecular docking studies, in order to identify inhibitors of E-channel which would meet the above criteria. The inhibitors are discussed below, organized by study.

Canrong Wu et al. [1]

Wu and his colleagues are scientists at Tongji Medical College in Wuhan, China. This molecular docking study is unusual in that it docked a wide range of compounds against 21 targets, including NSPs, structural proteins, ACE2, TMPRSS2 and the E-channel. The study examined 23 drugs and 11 natural products. (The full list is in the supplemental materials.) Of natural compounds, three stand out as safe and widely available:

1. hesperidin
2. lutein
3. phyllaemblicin G7
4. theaflavin 3,3′-di-O-gallate (TFDG)

Hesperidin is available as an OTC supplement. It is often used as a health supplement in combination with diosmin allegedly for the health of blood vessels and the lymphatic system. Theaflavin di-gallate (TFDG) is a component of black tea. It is available as a supplement called “Theaflavin” or “Theaflavin extract”. Phyllaemblicin G7 is not available as a separate supplement, but is a component of Amla (Indian Gooseberry), a widely used food in India and Southeast Asia. Amla is also available as a powder made from the berry. Lutein was listed by Wu as an inhibitor from the ZINC drug database, but it is a natural compound found in dark leafy greens. Lutein along with zeaxanthin is often taken for the health of the retina of the eye. The above are four natural compounds which are generally safe for healthy adults, at least as they are typically used.

As for their binding affinity, Wu characterized high effectiveness as an inhibitor as either a mean force Score (mfScore) of less than or equal to -150 or a docking score of less than or equal to -35. All four had mfScores of less than -150, and lutein also had a docking score of less than -35. (See the supplementary materials for details.)

Many molecular docking studies have found that hesperidin would be an effective inhibitor of multiple targets in SARS-CoV-2. If it also inhibits the E-channel, it will be all the more helpful against Covid-19. However, hesperidin is not very water soluble. As a supplement for blood vessel health, hesperidin methylchalcone is sometimes used instead, as it is highly water soluble. However, no published molecular docking studies have so far analyzed this compound as an inhibitor of SARS-CoV-2.

Lutein is insoluble in water, and so its effectiveness against SARS-CoV-2 in vivo is questionable. How much lutein will enter the cytoplasm, especially in the lungs, where it would be needed against the virus? The answer is unknown. Lutein supplementation is good for the eyes; it is doubtful that it will be of much help against Covid-19.

Phyllaemblicin G7 is a component of Amla (Indian Gooseberry). The amount of this compound in any dose of Amla powder, used as a supplement, is unknown. Also, the compound does not appear to be very soluble in water. Amal may be helpful against Covid-19, as multiple studies have found that it contains several compounds which are candidates for natural inhibitors of the virus. But the previously mentioned factors prevent it from being recommended above more likely choices.

Theaflavin digallate is mentioned by many molecular docking studies as a good inhibitor of multiple SARS-CoV-2 components. It is water soluble, and is available in black tea, per se, as a drink, as well as in supplement form. Of the four natural compounds which this study found to be good inhibitors of E-channel, TFDG is the most likely to be effective. It is best obtained in supplement form, as decaffeinated black tea contains little theaflavin, and the amount of regular black tea that one could reasonably consume is limited by the caffeine.

In addition to the natural compounds above, Wu et al. identified several drugs as possible inhibitors of E-channel:

Drug Score mean force Score

Cobicistat -33.89 -266.19
Lopinavir -30.30 -221.79
Suramin -46.40 -220.73

Ritonavir -25.60 -277.77
Atazanavir -23.75 -260.77
Nelfinavir -27.98 -206.77
Telaprevir -27.72 -201.60
Saquinavir -21.68 -189.04
Tipranavir -23.07 -176.00
Indinavir -15.93 -164.98
Beclabuvir -29.13 -164.50
maraviroc -19.49 -159.15

Scores above 30 are good; mean force Scores above 100 are good. Three drugs had both a Score above 30 and a mfScore above 100: cobicistat (an HIV drug), lopinavir (currently used against Covid-19), and suramin. The latter is a treatment for African sleeping sickness with substantial side effects, so it cannot be recommended for Covid-19. Since lopinavir is already used for Covid, along with ritonavir. The combination may be effective against the E-channel, perhaps decreasing risk of cytokine storm. A clinical study, perhaps retrospective, might determine whether patients receiving the combination had a lower risk of cytokine storm.

S. Borkotoky and M. Banerjee [2]

These authors sought inhibitors of the E-protein and the M-protein of SARS-CoV-2 within components of Azadirachta indica (Neem). The leaves of the neem tree are a widely-used health supplement, available OTC. The shoots and flowers of the tree are eaten as a vegetable. Neem oil can cause serious harm to health, if taken in excess.

The five strongest inhibitors of E-channel (and their docking scores) in this study were:
1. Nimbolin A (-11.2)
2. Nimocin (-11.0)
3. 7-Deacetyl-7-Benzoylgedunin (-10.9)
4. 24-Methylenecycloartanol (-10.8)
5. Cycloeucalenone (-10.5)

Although neem is available as an OTC supplement, in the form of leaf powder or neem oil, the amounts of each of the above compounds in the supplement are unknown. However, the docking scores are quite low, indicating high binding affinity. So these compounds deserver further study as inhibitors of E-protein.

Gupta et al. [3]

This study found that famotidine was a strong inhibitor of PLpro and a moderate inhibitor of Replicase and Nsp14. However, the drug inhibited the E-protein only mildly, at -4.60 kcal/mol. [114]

famotidine -4.60

Famotidine may be helpful in cases of Covid-19, but not as an inhibitor of E-channel, as the effect is too limited, and the concentration of famotidine from typical doses is too low.

Anatoly Chernyshev [4]

This molecular docking studies found 36 compounds that inhibit the E channel of SARS-CoV-2. However, many are strong medications with substantial side effects and contraindications. The mildest of the compounds is perhaps cepharanthine, which had a docking score of -11.5 kcal/mol.

cepharanthine -11.5

The study states that cepharanthine is an “alkaloid from Stephania cepharantha, used in Japan for more than 40 years for a wide variety of acute and chronic diseases. Inhibits cytokine production, scavenges free radicals and to have a protective effect against responses mediated by pro-inflammatory cytokines. No safety issues and rarely any side effects have been observed with cepharanthine.” [130]

Two other compounds mentioned in this study are often discussed as possible inhibitors of SARS-CoV-2: glycyrrhizic acid (-10.6) and its aglycon, enoxolone (-10.2) also known as glycyrrhetinic acid or glycyrrhetic acid. Glycyrrhizic acid is found in natural licorice extract. However, in excess it can have serious and even life-threatening side effects: high blood pressure, low potassium, heart arrhythmias, weakness, paralysis, and possibly brain damage. Yet this compound is often found in Chinese traditional herbal medicines. Given that there are safer compounds which also function as effective inhibitors of SARS-CoV-2, we should avoid this danger and make the safer choices.

Update 10 July 2020

A newly-released study of inhibitors of the Envelope, Membrane, and Nucleocapsid proteins found additional useful inhibitors of each [5].

Envelope protein (E-channel)
Rutin -9.3
Doxycycline -9.1

Membrane protein
Caffeic acid -8.4
Ferulic acid -8.3

Nucleocapsid protein
Rutin -7.9
Caffeic acid -7.4
Ferulic acid -7.2

If it is the case that doxycycline inhibits the E-channel strongly, as a docking score of -9.1 suggests, it might help reduce the risk of a cytokine storm. There is a bias in modern medicine against natural supplements and in favor of prescription medications. But if doxycycline works, and physicians are willing to prescribe it, fine.

Rutin is problematic as much of the compound is processed by the human digestive system so as to remove the sugar group, turning rutin into quercetin. Since this is a docking study, not a clinical study, that factor was not taken into account. It is likely that no enough rutin will reach the bloodstream so as to inhibit the virus, so doxycycline is the better choice.

Additional Natural Inhibitors

This author is working on a comprehensive review of molecular docking studies, compiling natural inhibitors of SARS-CoV-2 targets. As the work continues, any additional inhibitors of E-channel will be added to this article. Further work is needed to identify if lopinavir and ritonavir or possibly doxycycline might reduce risk of the cytokine storm, and whether neem extract may be a useful natural inhibitor of Covid-19.

Clinical studies are needed to confirms the above results. In the meantime, do not take any of these compounds as treatments for Covid-19, unless prescribed by your healthcare provider.

Ronald L. Conte Jr.
Covid.us.org
Note: the author of this article is not a doctor, nurse, or healthcare provider.

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1. Wu, Canrong, et al. “Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods.” Acta Pharmaceutica Sinica B (2020).

2. Borkotoky, Subhomoi, and Manidipa Banerjee. “A computational prediction of SARS-CoV-2 structural protein inhibitors from Azadirachta indica (Neem).” Journal of Biomolecular Structure and Dynamics just-accepted (2020): 1-17.

3. Gupta, Parth Sarthi Sen, et al. “Molecular Mechanism of Clinically Oriented Drug Famotidine with the Identified Potential Target of SARS-CoV-2.”

4. Chernyshev, Anatoly. “Pharmaceutical Targeting the Envelope Protein of SARS-CoV-2: the Screening for Inhibitors in Approved Drugs.” (2020).

5. Bhowmik, Deep, et al. “Identification of potential inhibitors against SARS-CoV-2 by targeting proteins responsible for envelope formation and virion assembly using docking based virtual screening, and pharmacokinetics approaches.” Infection, Genetics and Evolution (2020): 104451.