Green Tea Extract

Green tea is a hot drink made with the same type of leaves as black tea, but the leaves are processed without the withering and oxidation used to make black tea. This results in a different set of healthy polyphenols in green tea as opposed to black tea. Green tea is high in epigallocatechin gallate (EGCG) and other catechins; black tea has some EGCG, but it also offers theaflavin, found only in regular black tea. The decaffeinated versions of green tea and black tea have far less of the healthy polyphenols, far less EGCG, catechin, and theaflavins. So the caffeinated versions of green tea and black tea are much healthier. There are many studies showing the benefits of drinking green tea [4]. But you can only drink so much caffeine.

The benefits of a Green Tea Extract is it has the healthy compounds found in the regular tea, without the caffeine or the large amount of liquid. A 400 mg pill of Green Tea Extract (GTE) is the equivalent of about 3 cups of regular green tea. The typical Green Tea Extract (GTE) pil contains about 50% EGCG (epigallocatechin gallate) and another 30% other catechins. Be certain you are getting GTE which is in a “decaffeinated” form, so that you obtain the beneficial compounds (various catechins) without excess caffeine. Even so, the decaffeinated GTE will have a small amount of caffeine, usually just a few mg per pill.

The following amounts of EGCG (epigallocatechin 3-gallate) in different teas are from the USDA Flavonoid database [10].

In mg of flavonoids per cup of tea, with 1.0 g leaves/cup, EGCG:
9.36 Black tea, regular
1.01 Black tea, decaf
0.51 Black tea, ready-to-drink
0.00 Tea, iced, lemon flavor, ready-to-drink
0.45 Tea, instant, decaf
70.20 Green tea, regular
19.97 Green tea, regular, flavored
26.05 Green tea, decaf
68.20 Green tea, large leaf, Quingmao
3.96 Green tea, ready-to-drink
34.48 Tea, Oolong, regular
42.45 Tea, White, regular

The best teas for EGCG, in order, are green tea, large leaf green tea, white tea, oolong tea, and decaf green tea. Decaffeination reduces the amount of healthy flavonoids in any type of tea. Note, however, that Black tea and Puer tea have other compounds, apart from EGCG, which may inhibit viral components.

Covid-19 and SARS

Covid-19 is caused by the virus called SARS-CoV-2 (“the Coronavirus”). SARS is caused by the virus called SARS-CoV or SARS-CoV-1. The two viruses are similar, and so researchers began their search for treatments of SARS-CoV-2 by looking at the research on SARS-CoV-1. One of the compounds found to be effective against SARS was zinc ions. But zinc requires an ionophore to carry the zinc ions past the lipid bilayer of the cell membrane into the cytoplasm of human cells. EGCG, a component of Green Tea Extract (GTE), is one such zinc ionophore.

The EGCG can latch on to the zinc ion and carry it into the cell cytoplasm, where the zinc inhibits a viral protein called replicase. Replicase (or RdRp) makes copies of viral RNA. Both SARS-CoV-1 and SARS-CoV-2 have a replicase protein. The replicase protein complex (made up of several proteins) is blocked by zinc ions, preventing the virus from making copies of its RNA. This stops the virus from multiplying.

Further research on SARS-CoV-1 and SARS-CoV-2 and GTE found that EGCG (epigallocatechin gallate) and other Catechins are able to inhibit the virus directly, even without zinc. The various forms of catechin are able to bind to different viral proteins, to prevent them from working, thereby stopping the infection of cells or the replication of the virus within infected cells. So EGCG and the other Catechins have multiple viral targets which they can inhibit directly, and, in addition, EGCG can carry zinc into the cell, where the zinc inhibits replicase.

Molecular Docking Studies and Inhibitors

A molecular docking study is a three-dimensional computer simulation which typically tests various small molecules, compounds ranging from vitamins to natural supplements to medications, against various viral components, to determine which molecules might shut down a viral protein, thereby slowing the disease. These molecules must have the right shape and binding affinity (molecular attraction) to be able to bind to the protein in just the right place (e.g. the receptor binding domain) to stop the protein from working. The molecules are called ligands or inhibitors and the viral protein is called a target of inhibition.

As an analogy, suppose you forget to pay your parking tickets. The city will then put an “inhibitor” on the “receptor binding domain” of your car, to prevent it from working. And that’s what molecular docking studies look for: the right size and shape “boot” to attach to a viral protein’s “wheel” to keep it from working. Put a boot on enough viral proteins, and the disease becomes far less severe, thereby helping the immune system to clear the virus.

An IC50 is the concentration of the inhibitor needed to inhibit the virus or viral component to the extent of 50%. So if the goal is to prevent infection of cells, then the concentration needed to protect half the cells from infection is the IC50, usually measured in µM (micromolar) or sometimes in µg/ml. Of course, we want to inhibit the virus to as close to 100% as possible. But 50% provides a point of comparison between inhibitors. If one inhibitor has an IC50 of 200 µM and another of 20 µM, then it takes much less of the latter compound to inhibit the virus. (For example, quercetin has an IC50 of about 20 µM.)

My focus has been on search through molecular docking studies to find inhibitors which are natural safe OTC supplements. I’ve compiled a list of 175 molecular docking studies which identified one or more of this type of inhibitor. Here’s the List. If a reference number in this article says [mds #], then it is a reference to one of the studies on that particular page; the study will not be listed at the end of the article.

For EGCG and other Catechins found in GTE, there are over 50 molecular docking studies. And the studies have found that multiple Catechins, EGCG, CG, GCG, etc. are strong inhibitors against multiple proteins needed by SARS-CoV-2 to infect cells and to replicate in those cells. This fact makes is likely that GTE may be effective against SARS-CoV-2, as it contains multiple compounds which attack the virus and it is a zinc ionophore.

An inhibitor is a compound which binds to a viral protein in order to prevent that protein from working. For that reason inhibitors are also called ligands (referring to something that binds). An inhibitor might bind to the Spike protein on the outside of the Coronavirus (SARS-CoV-2), preventing that Spike from doing its job of connecting with a cell surface protein (ACE2) in order to infect the cell. But the inhibitor must bind to the right location, and must have a strong binding affinity for that “target” of inhibition.

But what can be done after the virus infects a cell? In that case, inhibitors are used which enter the cell and bind to any of the proteins used by the virus to make copies of itself within the cell. Since there are many viral components needed to infect a cell and to replicate in that cell, we need many different inhibitors or ligands to target each of the components. If we can find the right set of inhibitors, we can more effectively slow down the progress of the disease, Covid-19. Here is a list of the top targets, the most important viral components against which researchers are seeking inhibitors.

Targets of Inhibition

ACE2 – the normal human protein found on the surface of many cells; used as an entry point for SARS-CoV-2 to infect cells. Inhibition of ACE2 protects the cell from infection by SARS-CoV-2 (the Coronavirus).
Mpro – the main protease used by SARS-CoV-2 to make viral proteins
PLpro – the other protease used for the same purpose
RdRp – also called Replicase – makes copies of the viral RNA in order to make new copies of the virus in infected cells.
N-protein – wraps and protects the viral RNA.
Mpro, PLpro, and N-protein are also implicated in the virus’ attack on the immune system.
Spike protein – docks with ACE2 in order to infect cells; inhibition of Spike prevents infection
Other NSPs – other viral proteins named according to the numbering of the Non-Structural Protein genes, e.g. Nsp15, Nsp 16, etc.

Will This Approach Work?

Other viral diseases are treated with viral inhibitors. For example, HIV and Hepatitis C are both treated with FDA-approved prescription inhibitors [1, 2]. HIV is often treated with lopinavir and ritonavir [1]. Lopinavir is a viral protease inhibitor and ritonavir helps lopinavir remain in the body longer. These two HIV drugs are frequently repurposed for off-label use against COVID-19. Darunavir is another HIV protease inhibitor. Lopinavir inhibits and HIV protease called “3CLpro” and darunavir inhibits and HIV protease called “PLpro”. Proteases cut proteins to make smaller proteins or to activate a protein by changing its shape (by means of a cut). Both lopinavir and darunavir have been used against COVID-19 [3]. In the case of AIDS, this approach has had the effect of “transforming this deadly ailment into a more manageable chronic infection.” [1] Hepatitis C is commonly treated with protease and polymerase inhibitors [2]. A polymerase moves or changes RNA or DNA.

How Effective is GTE?

What can you expect from taking Green Tea Extract if you have Covid-19 or LongCovid? That is uncertain at this time. I know of no clinical studies using GTE or EGCG in Covid-19 patients. There is an in vitro study of EGCG as an effective inhibitor of SARS-CoV-2, the Covid-19 virus [15]. Another study reviews the anti-inflammatory and beneficial effects on the immune system that EGCG has [14]. But research on the components of GTE and their benefits for Covid-19 (or LongCovid) are very preliminary.

Currently, a prominent Covid-19 physician, Zev Zelenko, M.D. (https://twitter.com/zev_dr) recommends EGCG (found in GTE) as one of a few options for prophylaxis — for persons who are well and who wish to reduce their risk of Covid-19 infection and Covid-19 severity. See the interview of Dr. Zelenko by Dr. Mobeen Syed here.

EGCG is known to be a zinc ionophore: it helps transport zinc into the cells of your body; and it may be more effective in this role than quercetin [5, figure 6]. Once inside a cell, zinc may inhibit the viral protein called replicase. There are also studies showing that both EGCG and GCG directly inhibit Mpro (3CLpro) in SARS-CoV-1 [6], and that catechin gallate (CG) and gallocatechin gallate (GCG) both inhibit the N-protein (nucleocapsid protein) of SARS-CoV-1 [7]. The latter protein not only wraps and protects the viral RNA, but also works against the immune system once it is inside the cytoplasm of an infected cell [8, 9]. So a Green tea extract with EGCG and other Catechins would have multiple beneficial effects against SARS-CoV-1 and therefore possibly against SARS-CoV-2.

A molecular docking study specific to SARS-CoV-2 found that a component of regular green tea (EGCG) inhibits the PLpro viral component [11]. White tea and Oolong tea each have more epigallocatechin gallate than decaf green tea, but less than regular green tea; they each also have less of the flavonoids of black tea, so it is they are less helpful than black, Puer, or green tea. [10]

A different study showed that three different green tea compounds, listed below, inhibited two additional viral targets: 3CLpro and the N-protein. This suggests that green tea is effective against both proteases needed by the virus to replicate. The one study [11] was on SARS-CoV-2, and the other study [6] was on SARS-CoV-1.

The IC50 is the concentration of an inhibitor needed to inhibit 50% of the viral components (e.g. a protein) or inhibit 50% of the cell from being infected (depending on what the function of the specific inhibitor may be).

Inhibition of 3CLpro:
EpiGalloCatechin gallate (EGCG) — IC50 = 73 µM [6]
GalloCatechin gallate (GCG) — IC50 = 47 µM [6]

Inhibition of the N-protein (nucleocapsid)
(-)-catechin gallate (CG) and (-)-gallocatechin gallate (GCG) IC40 = 0.05 µg/ml [7]
Yes, that’s IC40 as in a 40% inhibition.

As noted immediately above, a study of SARS-CoV-1 found the following; “At a concentration of 0.05 µg/ml, (-)-catechin gallate and (-)-gallocatechin gallate showed more than 40% inhibition activity… [7]”. That is a remarkably low inhibition concentration, attesting to the high degree of efficacy of these two compounds. (A typical IC50 for an effective compound might be in the range of 10 to 50 µg/ml, and yet 0.05 µg/ml is 1/200th of 10 µg/ml.) The viral component inhibited was the N-protein that wraps the viral RNA and may have other functions. The study stated that the N-protein “is a major pathological determinant in the host and might cause host cell apoptosis, upregulate the pro-inflammatory cytokine production, and block innate immune responses. [7]”

So, inhibiting the N-protein may possibly reduce, to some extent, excess inflammatory reaction in the body caused by COVID-19. This is an important viral function to block, as it causes some of the more dangerous symptoms in patients with severe COVID-19. Which other supplements inhibit the N-protein, according to molecular docking studies? Not many: quercetin, procyanidin, famotidine, Piceatannol, and FAD (which your body makes from Vitamin B2, Riboflavin).

Cautions re: Green Tea Extract

Be advised that tea extracts and related supplements may present some risk of a danger to the liver [12], especially at high levels of intake or intake for months or more, and therefore should not be used by persons with liver problems. Green tea extract can interfere with some medications: caffeine can interfere with “drugs that are MAO inhibitors,” or that are “proteasome inhibitors (such as BZM, MG-262, and PS-IX),” and can reduce the absorption of the beta-blocker nadolol (Corgard), and “can affect the absorption of certain statin medications, depending on the dose of green tea, the type of statin medication, and individual differences.” Green tea cautions are from Consumerlab.com [13].

Molecular Docking Studies

Over 50 molecular docking studies found components of GTE to be effective as inhibitors of SARS-CoV-2 viral components, including the Spike protein, both proteases, Replicase, and others. The studies listed here correspond to the references numbered below as “mds #”.

mds 1 – Epigallocatechin gallate (EGCG), Epigallocatechin (EGC), and Catechin inhibit Mpro (main SARS-CoV-2 protease)

mds 5 – Catechin inhibits Mpro and strongly inhibits RdRp (replicase)

mds 7 – EGCG inhibits PLpro (the other SARS-CoV-2 protease)

mds 14 – EGCG strongly inhibits Spike protein.

mds 15 – Catechin, Catechin gallate, Epicatechin gallate, Epigallocatechin, Epigallocatechin gallate (EGCG), Gallocatechin, and Gallocatechin gallate inhibited the Spike protein, preventing attachment of the Spike to ACE2.

mds 16 – EGCG strongly inhibits Mpro

mds 17 – EGCG strongly inhibits Spike protein; EGCG and GCG inhibit ACE2

The rest of the studies found similar results, various components of GTE inhibit multiple components of SARS-CoV-2:
mds 18, 20 through 34, 36-39, 47, 54, 56, 66, 67, 69, 75, 78, 102, 104, 105, 110, 120, 128, 133, 137, 146, 154, 158, 160, 161, 164, 166, 168, 172, 176. All of the aforementioned studies are found on this page: The Covid-19 Molecular Docking Studies List

Molecular docking studies are simulation on a computer, so you might question whether the findings correspond to the real world. But the number of the studies and the number of researchers involved make the results more convincing. This is not merely one or a few studies; it is hundreds of researchers obtaining the same results. In addition, there are some in vitro studies and recommendations from physicians, as discussed previously. Green Tea Extract is not a cure for anything; but it may be a helpful as a preventative measure, or as an adjunct to whatever other treatments a Covid-19 or LongCovid patient is taking.

Ronald L. Conte Jr.
Covid.us.org
Note that I’m an author, not a physician.

ENDNOTES:

[1] Ghosh, Arun K., Heather L. Osswald, and Gary Prato. “Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS.” Journal of medicinal chemistry 59.11 (2016): 5172-5208.

[2] Zaj?c, Marianna, et al. “Hepatitis C-New drugs and treatment prospects.” European journal of medicinal chemistry 165 (2019): 225-249.

[3] Lin, Shen, Runnan Shen, and Xushun Guo. “Molecular Modeling Evaluation of the Binding Abilities of Ritonavir and Lopinavir to Wuhan Pneumonia Coronavirus Proteases.” bioRxiv (2020).

[4] Conte, Ronald L., Jr. Healthy Eating versus Mortality, Available at Amazon.com.

[5] Dabbagh-Bazarbachi, Husam, et al. “Zinc ionophore activity of quercetin and epigallocatechin-gallate: From Hepa 1-6 cells to a liposome model.” Journal of agricultural and food chemistry 62.32 (2014): 8085-8093.

[6] Nguyen, Thi Thanh Hanh, et al. “Flavonoid-mediated inhibition of SARS coronavirus 3C-like protease expressed in Pichia pastoris.” Biotechnology letters 34.5 (2012): 831-838.

[7] Roh, Changhyun. “A facile inhibitor screening of SARS coronavirus N protein using nanoparticle-based RNA oligonucleotide.” International journal of nanomedicine 7 (2012): 2173.

[8] 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.

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

[10] USDA Flavonoid Database: Bhagwat, Seema, David B. Haytowitz, and Joanne M. Holden. “USDA database for the flavonoid content of selected foods, Release 3.1.” US Department of Agriculture: Beltsville, MD, USA (2014). PDF file

[11] 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).

[12] Yao, Xueting, et al. “In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).” Clinical Infectious Diseases (2020).

[13] Consumerlab.com, Green Tea Review: Supplements, Brewable, Matcha, and Bottled; Cautions. PDF file

[14] Menegazzi, Marta, et al. “Protective Effect of Epigallocatechin-3-Gallate (EGCG) in Diseases with Uncontrolled Immune Activation: Could Such a Scenario Be Helpful to Counteract COVID-19?.” International Journal of Molecular Sciences 21.14 (2020): 5171.

[15] Jang, Minsu, et al. “Tea Polyphenols EGCG and Theaflavin Inhibit the Activity of SARS-CoV-2 3CL-Protease In Vitro.” Evidence-Based Complementary and Alternative Medicine 2020 (2020).