by Michael Stanclift, ND
Introduction
While vaccines and targeted therapies are in development for the treatment of COVID-19, some researchers are looking to known natural molecules as therapeutic agents. Two promising treatments for COVID-19, hydroxychloroquine and ivermectin, are derivatives of naturally occurring substances.
Some researchers are interested in a compound from green tea with antiviral and anti-inflammatory properties. Chemists looking at computer models of the virus (SARS-CoV-2) that causes COVID-19 believe epigallocatechin gallate (EGCG) from green tea will have high binding affinity for SARS-CoV-2, as they explain in a preliminary report.1 It’s important to state that COVID-19 has no known universally accepted treatment or cure at the time of publication. There is no clinical evidence that EGCG can prevent, treat, or cure COVID-19. The information in this article is intended for use by licensed healthcare professionals for educational purposes only and should not be used to treat, and/or diagnose any medical condition(s).
Antiviral mechanisms of action
In preclinical research EGCG shows broad antiviral mechanisms for an array of viruses that affect human health.3 EGCG also has the advantage of being active across a range of cells, from viral host cells to immune cells.3,4 The virus that causes COVID-19 is a positive-sense single-stranded RNA virus, which puts it in a similar classification as hepatitis C, Zika, and West Nile viruses.2,3 EGCG is known to inhibit viral entry of hepatitis C and Zika, but the effect is not known for SARS-CoV-2.3 SARS-CoV-2 enters cells through the angiotensin-converting enzyme-2 (ACE2) receptor on the surface of lung cells, and one study suggests EGCG may have some ACE-inhibitory activity, especially at higher concentrations.5,6 We know that EGCG does not inhibit a specific target (3CLpro) that was found on SARS-CoV (that caused a 2003 outbreak) and has also been identified as a target for SARS-CoV-2.7,8 Another compound in tea, TF3, does show inhibition of this target.7
A review of EGCG’s antiviral mechanisms shows it has either direct or indirect antiviral activity against:3,9
DNA viruses:
-
- Herpes simplex virus (HSV)
- Adenovirus
- Human papilloma virus (HPV)
- Hepatitis B virus (HBV)
- Epstein-Barr virus (EBV)
(+)ssRNA viruses:
-
- Hepatitis C virus (HCV)
- Zika virus (ZIKV)
- Dengue virus (DENV)
- West Nile virus (WNV)
- Chikungunya virus (CHIKV)
- Porcine Reproductive and Respiratory virus (PRRS)
- Enterovirus
- Japanese encephalitis virus (JEV)
- Tick-borne encephalitis virus (TBEV)
(-)ssRNA viruses:
-
- Human immunodeficiency virus (HIV)
- Ebola virus (EBOV)
- Influenza virus
Double-stranded RNA virus:
-
- Rotavirus
A randomized placebo-controlled trial (n = 197) investigating the antiviral effects of EGCG showed a 75% reduction in the rates of clinically defined influenza infection among healthcare workers.10
Figure: Antiviral mechanisms9
Anti-inflammatory mechanisms of action
Mechanistic studies of EGCG’s anti-inflammatory actions make it an attractive molecule for modulating cytokines and the effects of these signaling molecules.
The cytokine storm of COVID-19 involves IL-2, IL-6, IL-7, granulocyte-colony stimulating factor (GCSF), interferon-gamma inducible protein 10 (IP-10/CXCL10), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1-alpha (MIP-1α), tumor necrosis factor-alpha (TNF-α), and janus kinase (JAK).11 EGCG cannot reduce all of these cytokines and may increase some of them.4
EGCG can inhibit these inflammatory enzymes and cytokine/chemokine signals:
-
- COX-112
- COX-213 (conflicting data)4
- IFN-γ4
- IL-1β13 (conflicting data)4
- LTB412
- MCP-114
- NF-κB15
- NLRP316
- TNF-α17 (conflicting data)4
In connection to the effects on cytokines, EGCG has effects on the behavior of both innate and adaptive immune cells as described in the table below.4
| Immune Cell Type | Effect from EGCG |
| Neutrophil | ↓ Recruitment |
| Monocyte/Macrophage | ↓ Chemotaxis |
| Dendritic Cell | ↓ Maturation, MHC class II, IL-12 |
| T-Cell |
↓ Proliferation ↓ IFN-γ, Zap70, LAT, PLC-γ ↓Th-1, Th-9, Th-17 cells ↑T-reg cells |
| B-Cell | ↓ Proliferation |
Dosage and absorption
EGCG is predominantly found in green tea, but is also found in other foods such as apples, kiwi, strawberries, hazelnuts, pecans, etc., in smaller amounts. A 250 mL cup of brewed green tea has approximately 25-60 mg of EGCG (roughly 50-60% of the catechins are EGCG).18,19 Several studies found EGCG levels in the blood reach higher levels when taken with a meal or other nutrients.20,21 EGCG has a wide therapeutic window, with single or divided doses from 150-2,400 mg being studied in subjects without serious adverse effects.19 If taken as green tea, caffeine consumption should be monitored.
Interactions
EGCG inhibits P-glycoprotein, organic anion-transporting polypeptide (OATP1A2, OATP1B1, OATP2B1), and cytochrome P450 (CYP1A2, CYP2C9, CYP3A4).22,23 Patients taking any drugs metabolized by these should be monitored. EGCG may also interact with bortezomib, blocking its activity.19
Conclusion
The antiviral and anti-inflammatory effects of EGCG demonstrate its broad utility for human health. Not discussed in this article are its use in other diseases, such as bacterial infections, cardiovascular disease, obesity, autoimmune conditions, and cancer. However, it’s important to note that the effects of EGCG on COVID-19 are unknown. At time of publication there are no registered clinical trials investigating EGCG in the prevention or treatment of COVID-19. It appears to be effective at preventing respiratory infections including influenza in human clinical trials, which are cooccurring with COVID-19.10,24 Clinicians and researchers must consider the underlying mechanisms of disease and therapeutics when making clinical decisions. EGCG is certainly worthy of attention for its safety profile and broad applicability in fighting certain viral and inflammatory conditions.
Citations
- Khan MF et al. Identification of dietary molecules as therapeutic agents to combat COVID-19 using molecular docking studies. Computational Chemistry. Prepublication. Available at: https://www.researchsquare.com/article/rs-19560/v1. Accessed April 9, 2020.
- Lu R et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. 2020;395(10224):565-574.
- Kaihatsu K et al. Antiviral mechanism of action of epigallocatechin-3-o-gallate and its fatty acid esters. 2018;23(10):2475.
- Wu D et al. Nutritional modulation of immune function: analysis of evidence, mechanisms, and clinical relevance. Front Immunol. 2019;9:3160.
- Hoffmann M al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. 2020;S0092-8674(20)30229-4.
- Guerrero L et al. Inhibition of angiotensin-converting enzyme activity by flavonoids: structure-activity relationship studies. PLoS One. 2012;7(11):e49493.
- Chen CN et al. Inhibition of SARS-CoV 3C-like protease activity by theaflavin-3,3′-digallate (TF3). Evid Based Complement Alternat Med. 2005;2(2):209–215.
- Duan Y et al. Advance of promising targets and agents against 2019-nCoV in China. Drug Discov Today. 2020;S1359-6446(20)30098-2.
- Xu J et al. A review of the antiviral role of green tea catechins. 2017;22(8):1337.
- Matsumoto K et al. Effects of green tea catechins and theanine on preventing influenza infection among healthcare workers: a randomized controlled trial. BMC Complement Altern Med. 2011;11:15.
- Mehta P et al. COVID-19: consider cytokine storm syndromes and immunosuppression. 2020;395(10229):1033-1034.
- Mohseni H et al. COX-2 inhibition demonstrates potent anti-proliferative effects on bladder cancer in vitro. J Surg Res. 2004;119(2):138-142.
- Choi JH et al. Effects of green tea catechin on polymorphonuclear leukocyte 5′-lipoxygenase activity,leukotriene B4 synthesis, and renal damage in diabetic rats. Ann Nutr Metab. 2004;48(3):151-155.
- Melgarejo E et al. Epigallocatechin gallate reduces human monocyte mobility and adhesion in vitro. Br J Pharmacol. 2009;158(7):1705–1712.
- Babu PV et al. Green tea catechins and cardiovascular health: an update. Curr Med Chem. 2008;15(18):1840–1850.
- Lee HE et al. Epigallocatechin-3-gallate prevents acute gout by suppressing NLRP3 inflammasome activation and mitochondrial DNA synthesis. 2019;24(11):2138.
- Haghighatdoost F et al. The effect of green tea on inflammatory mediators: A systematic review and meta-analysis of randomized clinical trials. Phytother Res. 2019;33(9):2274-2287.
- Jówko E. Green Tea Catechins and Sport Performance. In: Lamprecht M, editor. Antioxidants in Sport Nutrition. Boca Raton (FL): CRC Press/Taylor & Francis; 2015. Chapter 8. Available from: https://www.ncbi.nlm.nih.gov/books/NBK299060/
- Green tea. Natural medicines. https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=960. Accessed April 11, 2020.
- Gawande S et al. Effect of nutrient mixture and black grapes on the pharmacokinetics of orally administered (-)epigallocatechin-3-gallate from green tea extract: a human study. Phytother Res. 2008;22(6):802-808.
- Miller RJ et al. A preliminary investigation of the impact of catechol-O-methyltransferase genotype on the absorption and metabolism of green tea catechins. Eur J Nutr. 2012;51(1):47-55.
- Kim TE et al. Effect of epigallocatechin-3-gallate, major ingredient of green tea, on the pharmacokinetics of rosuvastatin in healthy volunteers. Drug Des Devel Ther. 2017;11:1409–1416.
- Satoh T et al. Inhibitory effects of eight green tea catechins on cytochrome P450 1A2, 2C9, 2D6, and 3A4 activities. J Pharm Pharm Sci. 2016;19(2):188-197.
- Rowe CA et al. Specific formulation of Camellia sinensis prevents cold and flu symptoms and enhances gamma,delta T cell function: a randomized, double-blind, placebo-controlled study. J Am Coll Nutr. 2007;26(5):445-452.
Michael Stanclift, ND graduated from Bastyr University’s school of naturopathic medicine and practiced in Edinburgh, Scotland, and Southern California. He enjoys educating other healthcare providers and impacting the lives of their many patients. When he’s not working, he spends his hours with his wife and two children.
Hi, just thought i’d share my anecdote, this does seem to work and keep certain viruses mild , as i have been having EGCG ( as green tea ) for over approx 10 years and while having it i haven’t been ill with Flu , don’t get common cold and not been ill with COVID 19 ( yet ) if i’ve had it i haven’t realised. I have it as strong green tea couple of times a day, to stop it getting a proper hold, ( hard to actually stop it entering your body, as you know but once its in there you can fight it) if i do feel like i have something starting to invade my body , i do generally up the amount to 3 or 4 ( not had to go to 4 much ) strong cups a day, then that feeling seems to go after a day, with no symptoms getting past very mild. i’m really interested in microbiology , virology so i do research this type of thing a lot and if i can i do try things out myself, nothing to lose by trying something if i can.