Disclaimer: Natural inhibitors are not a treatment or cure for Covid-19, nor for any other disease. Studies on natural inhibitors are very preliminary and do not yet include any clinical studies.

An inhibitor is a medication or a natural supplement which binds to a viral protein to interfere with the function of that viral protein. Inhibiting a viral protein in this way can interfere with the viral infection of cells, or with the replication of the virus in an infected cell. Some inhibitors instead bind to normal proteins in the human body, thereby protecting the protein from the virus.

The inhibitor can be a vitamin, a mineral, a natural compound from a plant, or an artificial chemical (a drug or medication). The inhibitor is also called a “ligand” because it binds to the protein. The effectiveness of each inhibitor is matter of percentages; no inhibitor is 100% effective. Therefore, to be most effective, a set of inhibitors, targeting a set of different viral components is needed.

This article is about using natural inhibitors to target viral components. The inhibitor binds to and deactivates those viral components, thereby slowing the progression of the disease. This may enable the immune system to better fight the virus, possibly making the disease less severe and shortening the time to recovery.

In order to know which inhibitors to choose, we have to understand what each viral component does, so as to know what to target for inhibition. And we have to understand the degree of effectiveness of each natural inhibitor. To evaluate the effectiveness of inhibitors against viral components, we rely first on molecular docking studies. This is the most preliminary type of study seeking viral inhibitors.

A molecular docking study is a computer analysis, typically of two things, a protein and a small molecule. The protein is usually a viral component and the small molecule is usually a medication or a natural supplement. The goal is to find small molecules which will bind to the protein in just the right location to prevent it from working. Binding in the wrong location would be ineffective. Binding too loosely will also fail.

For example, hesperidin can attach to the “receptor binding domain” of the Spike protein of the Coronavirus (SARS-CoV-2). Theoretically, this should reduce the infectivity of the virus as the connection between the Spike and the cell’s ACE2 receptor is blocked.

Analogy: Let’s say that you forget to pay your parking tickets. The city will then put an “inhibitor” on the “receptor binding domain” of your motor vehicle, to prevent it from working. In other words, the city will “boot” your car’s wheel, until you pay the tickets. That is what we want to do with the Coronavirus. We want to boot as many viral components as we can, in order to shut down the virus, so that the immune system can catch up with the disease and clear your body of the virus, hopefully.

I have gathered a set of over 140 molecular docking studies which test various natural products, most of them from plant sources, against different viral components as targets for inhibition. Across these many studies, I’ve found that certain natural compounds are identified, again and again as effective inhibitors; many of these are available as over-the-counter supplements. Some of these natural products are already taken by many persons as health supplements. However, clinical studies confirming the results of these computer studies are still lacking.

Targets for Inhibition

The Coronavirus is officially called SARS-CoV-2. It’s called that because it resembles the virus that causes SARS, SARS-CoV-1 (or simply SARS-CoV). The disease the Coronavirus causes is called Covid-19, which stands for: Corona Virus Disease 2019.

The virus is a spherical shape, with a membrane made from a lipid bilayer. That is the same stuff that the cells of the human body are made of, so the immune system is unable to recognize that lipid bilayer as foreign.

The sphere has proteins embedded in it:

S – The Spike protein, which connects with a protein called the ACE2 receptor protein, found on the surface of certain cells. This connection initiates a fusion between the viral membrane and the cell wall (because both are lipid bilayers). The virus then drops its RNA into the cytoplasm of the cell. That is how SARS-CoV-2 infects human cells, via its Spike protein or S-protein.

Inhibition of the Spike protein reduces the percentage of cells that will be infected the virus, as the inhibitor blocks the Spike from connecting with the ACE2 receptor. The Spike is a major target for inhibition because this will reduce the percentage of cells infected and thereby reduce viral load (the amount of virus in the body).

E – The Envelope protein or E-channel is a literal channel permitting ions, such as Calcium and Magnesium, to enter and leave through the viral membrane. A recent study concluded that this E-protein by itself was sufficient to cause the cytokine storm of Covid-19, which is what kills many patients [1].

Cytokine Storm – cytokines are signaling proteins used by the immune system to control the cells that fight against disease. The cytokines are sent out, and then they signal for different immune system players to become more active and to fight the infection in various ways. However, an excess of cytokines leads to an over-reaction which can result in death. Excess cytokines can cause blood vessel expansion in the lungs, making the vessels leaky; fluid will then fill the lungs, causing pneumonia. Some kinds of cytokines actually trigger cell death. The normal role this has is to kill cells that are infected (or cancerous). This can help clear a disease from the body. But excess cytokines of this type can cause the loss of a lot of tissue. A cytokine storm also has effects on inflammation, blood pressure, and effects on the heart, kidneys, and other major organs, which can cause shock and organ shutdown and death.

Inhibition of the E-channel might possibly reduce the risk of a cytokine storm, thereby reducing risk of death. This is only a theory at present [1]. And the exact function of the E-channel is not clear. Why does the virus need a channel to let calcium and magnesium into and out of the viral membrane?

M – The Membrane protein or M-protein binds the viral RNA, inside the virus, to the membrane. The RNA inside the virus is itself wrapped and protected by a Nucleocapsid protein, which is also called the….

N-protein. The M-protein binds the N-protein to the viral membrane, thereby securing the RNA inside. SARS-CoV-2 has a very large genome, that is to say, a very long RNA strand, and so it needs to be wrapped, protected, and secured in this manner.

Inhibition of the Membrane protein does not seem to be particularly useful. A molecule binding to the outside of the M-protein does not interfere with its function.

Inhibition of the N-protein can only occur after a cell is infected. The virus drops its RNA and the N-protein into the cytoplasm of the infected cell. The N-protein releases the viral RNA, and then the N-protein interferes with the cell’s RNA silencing system, which ordinarily would limit the amount of viral proteins that could be made [2]. In addition, the N-protein suppresses Interferon type I (IFN), disrupting the response of the immune system to the viral infection [3]. So when we inhibit the N-protein, the RNA silencing system remains active, reducing the amount of viral protein that can be made from the virus’ RNA, and Interferon type I is not suppressed, allowing the immune system to be more active in fighting the viral infection. Therefore, targeting the N-protein is important.

The above targets for inhibition are viral proteins. Another target is the ACE2 receptor. When an inhibitor binds to the ACE2 receptor, it prevents the Spike protein from connecting with ACE2, thereby preventing infection.

ACE2 – a protein normally found on the surface of cells in the lungs as well as the heart, kidneys, intestines, cells that line the blood vessels, some reproductive system cells, and nerve cells in the brain and central nervous system. The virus can infect any cell with an ACE2 protein at its surface, so it can infect a wide range of cells beyond the lungs. Infection of cells that line blood vessels can cause extensive coagulation of the blood, forming blood clots that destroy large amounts of tissue in the lungs, heart, and other organs.

When the virus infects a cell, the cell’s own machinery begins to make protein from the viral RNA. The proteins include 16 non-structural proteins (or NSPs), and a set of structural and accessory proteins, like the S, M, N, and E proteins. All of these proteins are potential targets for inhibition. Only the most important ones will be discussed in this article.

PLpro and Mpro (a.k.a. 3CLpro) are two viral proteases. A protease cuts or “cleaves” proteins into smaller pieces. In order to make a lot of protein quickly, SARS-CoV-2 makes two long do-nothing proteins (polypeptides 1a and 1b). Then the virus uses its two proteases to cut up those long proteins into 16 working proteins.

These two proteases (PLpro and Mpro) have a second function. They cut up normal human proteins used in the immune system [4]. This sabotages the immune system at an early point in its biochemical processes. The viral proteases cleave three immune system proteins (IRF3, NLRP12, and TAB1), causing two effects. First, the response of the innate arm of the immune system, which is the first responder to a viral or bacterial infection, is blunted. Second, the inflammatory response is increased, by enhanced production of Interleukin-6, to a harmful extent, making a cytokine storm more likely [4].

Inhibition of PLpro and Mpro is particularly important, as inhibition of these viral components should help to keep the immune system running properly and interfere with the virus making copies of itself.

Replicase (a.k.a. RdRp or Nsp12) is a protein which makes copies of the viral RNA. It reads the nucleotides on the RNA, and then makes a complementary RNA strand. While it is doing so, a second protein called an exonuclease (ExoN or Nsp14) proof-reads the new RNA strand, kicking out any errors.

Inhibition of Replicase shuts down the replication of the viral RNA, preventing the virus from making copies of itself.

Helicase is a polymerase which helps the virus move around its RNA. When Replicase makes a complementary RNA strand, it is initially still attached to the strand being copied. These two RNA strands are called sense (the strand that makes protein) and antisense (the strand that doesn’t make protein). Helicase pulls these two strands apart, so that the antisense strand can be copied by Replicase, making a new sense strand and the sense strand can be copied also, making another antisense strand. Without a working Helicase, the viral RNA would remain as a double helix, which turns out to not be useful at all for single strand viruses.

Inhibition of Helicase stops viral replication as the two RNA strands remain stuck together. This is a less important target for inhibition, but useful if you have an effective inhibitor that has few mild side effects and is readily available.

These are the 8 most important targets for inhibition:
a. Spike protein
b. ACE2
c. E-channel
d. N-protein
e. PLpro
f. Mpro
g. Replicase
h. Helicase

Finding the Right Inhibitors

Molecular docking studies have identified many different compounds which inhibit these targets. These inhibitors will not necessarily work in vivo. Studies of the SARS virus sometimes showed that compounds which seemed effective in molecular docking studies did not work when in vitro studies tested those compounds against the virus. And then, subsequent to in vitro studies, clinical studies would be needed to determine which compounds work best in human persons.

The above is part one of this article. Part two will examine the top candidates for natural inhibitors of each of the above targets of inhibition. I am preparing a couple of spreadsheets based on over 140 different molecular docking studies. The second part of the article will be based on those studies, and will discuss which inhibitors might be the best candidates for a clinical trial.

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

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1. Gao, Zhaobing, et al. “SARS-CoV-2 envelope protein causes acute respiratory distress syndrome (ARDS)-like pathological damage and constitutes an antiviral target.” bioRxiv (2020).

2. Mu, Jingfang, et al. “SARS-CoV-2-encoded nucleocapsid protein acts as a viral suppressor of RNA interference in cells.” Science China Life Sciences (2020): 1-4.

3. Chen, Jidang, and Hinh Ly. “Immunosuppression by viral N proteins.” Oncotarget 8.31 (2017): 50331.

4. Moustaqil, Mehdi, et al. “SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts.” bioRxiv (2020).

5. Khater, Shradha, Nandini Dasgupta, and Gautam Das. “Combining SARS-CoV-2 proofreading exonuclease and RNA-dependent RNA polymerase inhibitors as a strategy to combat COVID-19: a high-throughput in silico screen.” (2020).