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Nature’s powerful antiviral secret.

Updated: Feb 18, 2021

If there was ever a question about how profoundly viral infections can affect human health and activity, the current SARS-CoV 2 (Covid 19) pandemic should have definitely put it to rest. Viruses are one of the most common pathogens and responsible for a tremendous number of deaths every year, partially due to their frequent mutations and periodic emergence from animal reservoirs.


To make matters worse, available treatments are good only for easing the symptoms and do not eliminate the cause. Vaccination is considered the most effective preventative measure but is available only for some virus strains.


The good news for this field, however, has been increasingly coming from the use of natural products, many of which have been used in traditional medicine for centuries. This comes as no surprise as natural phytochemicals - compounds derived from plants – are known for their role in drug discovery: over 40% of antiviral drugs in clinical use are natural products and 34% were designed based on natural products (1).



What is betulin?


One of these powerful natural compounds is betulin. It belongs to the class of natural compounds called triterpenes which are found in a great variety of fruits, vegetables and medicinal plants and are therefore part of the human diet. It turns out that the richest source of betulin (30 percent of dry weight) is the bark of the white birch tree (Betula species) (2).


Betulin has long been known for its antimicrobial qualities in various cultures around the world, but in recent years betulin and its close relative, betulinic acid (BA), have received widespread attention from the scientific and medical communities due to their metabolic, anticancer and antiviral properties.


Betulin and BA’s extensively researched antiviral activity is reflected in over 2,000 scientific articles published in peer-reviewed journals. Here are some of the notable findings:


● Betulinic acid was found to be one “of the two most potent compounds” among thousands that were screened for their ability to inhibit SARS-CoV, a coronavirus that existed before COVID 19 (3).

● In a clinical trial for the treatment of HIV, a derivative of betulinic acid was found to inhibit the maturation process of the virus (4).

● Further clinical research has suggested betulinic acid’s potential efficacy against chronic hepatitis C (5).

● Betulin and / or betulinic acid were also found to be active against:


○ Influenza Virus A ,

○ Herpes Simplex Virus-1

○ Herpes Simplex Virus-2

○ Herpes Zoster

○ Hepatitis B (6, 7, 8)


A breakthrough 2011 article from Cell Metabolism (9) has revealed an actual biological target of betulin - a protein called SREBP (Sterol Regulatory Element-Binding Protein) - which turned out to be one of the most powerful regulators of the fat metabolism in a cell.


This important finding -- crucial for understanding betulin’s amazing metabolic benefits - did not seem to be related to its known antiviral properties at first glance. However, by closely examining the life cycle of a virus, it becomes clear that suppression of fat production by betulin is likely the driving force behind its antiviral activity as well.


How does betulin work against viruses?

Viruses are very simple life forms that entirely rely on the cells they infect in order to survive and replicate. Once they’re inside the cell, they hijack the cellular machinery to create multiple copies of themselves. These copies will go on to infect more cells in the body.


For so-called “enveloped viruses” (among them are flu virus, HIV, coronavirus, Herpes, Hepatitis C, and Hepatitis B), this process involves an additional step of building a lipid (or fat)-based shell around their core before exiting the cell. Here is where betulin comes in: By inhibiting SREBP, it suppresses lipid (fat) production depriving a virus of its crucial structural element. Without these lipids as part of their coating, viruses are no longer functional and cannot propagate.


Fat suppression by betulin as a possible explanation of its antiviral properties was indirectly confirmed bya recent study by scientists at Mount Sinai Medical Center and at Hebrew University of Jerusalem, who screened a collection of drugs to identify an agent that would interfere with the ability of the SARS-CoV 2 (Covid-19) virus to reproduce (10).



They found that the known cholesterol-lowering drug fenofibrate made lung cells burn more fat, essentially depleting fat reserves needed for the viral lipid envelope, which led to dramatic reduction in the virus’s proliferation and improved the patients’ condition.


Also, in another study published in Nature, scientists demonstrated the necessity of the SREBP protein for the process of viral infection. They used betulin to convey that SREBP inhibitors are effective in decreasing viral proliferation, despite the primary focus of the article being a different SREBP inhibitor (11).


Universal threat to all enveloped viruses.


A great unsolved challenge in the world of viral infections is to find an antiviral treatment that would be universal to all (enveloped) viruses. Not only there are multiple types of viruses out there, each requiring its own vaccination strategy, but there are persistent genetic mutations within one type of virus that often make it extremely difficult to track. By hacking a fundamental process such as supply of building material for the virus’s lipid-made envelope, drugs like fenofibrate and plant products like betulin pose a viable threat to the uncontrolled spread of the viruses inside the body.


REFERENCES:

1. David J. Newman and Gordon M. Cragg, Journal of Natural Products, 2016, 79 (3), 629-661. https://doi.org/10.1021/acs.jnatprod.5b01055

2. Šiman, Pavel et al. “Effective Method of Purification of Betulin from Birch Bark: The Importance of Its Purity for Scientific and Medicinal Use.” PloS one vol. 11,5 e0154933. 6 May. 2016, https://doi.org/10.1371/journal.pone.0154933

3. Chih-Chun Wen, Yueh-Hsiung Kuo, Jia-Tsrong Jan, Po-Huang Liang, Sheng-Yang Wang, Hong-Gi Liu, Ching-Kuo Lee, Shang-Tzen Chang, Chih-Jung Kuo, Shoei-Sheng Lee, Chia-Chung Hou, Pei-Wen Hsiao, Shih-Chang Chien, Lie-Fen Shyur, and Ning-Sun Yang. Specific Plant Terpenoids and Lignoids Possess Potent Antiviral Activities against Severe Acute Respiratory Syndrome Coronavirus. Journal of Medicinal Chemistry 2007 50 (17), 4087-4095. https://doi.org/10.1021/jm070295s

4. Martin, D.E., Blum, R., Doto, J. et al. Multiple-Dose Pharmacokinetics and Safety of Bevirimat, a Novel Inhibitor of HIV Maturation, in Healthy Volunteers. Clin Pharmacokinet 46, 589–598 (2007). https://doi.org/10.2165/00003088-200746070-00004

5. Shikov AN, Djachuk GI, Sergeev DV, Pozharitskaya ON, Esaulenko EV, Kosman VM, Makarov VG. Birch bark extract as therapy for chronic hepatitis C--a pilot study. Phytomedicine. 2011 Jul 15;18(10):807-10. https://doi.org/10.1016/j.phymed.2011.01.021https://doi.org/10.1016/j.phymed.2011.01.021

6. Amiri, Shayan, et al. “Betulin and Its Derivatives as Novel Compounds with Different Pharmacological Effects” Biotechnology Advances, vol. 38, 2020. https://doi.org/10.1016/j.biotechadv.2019.06.008

7. Hong, E. H., Song, J. H., Kang, K. B., Sung, S. H., Ko, H. J., & Yang, H. (2015). Anti-Influenza Activity of Betulinic Acid from Zizyphus jujuba on Influenza A/PR/8 Virus. Biomolecules & therapeutics, 23(4), 345–349. https://doi.org/10.4062/biomolther.2015.019

8. Yao, D., Li, H., Gou, Y., Zhang, H., Vlessidis, A.G., Zhou, H., Evmiridis, N.P. and Liu, Z. (2009), Betulinic acid‐mediated inhibitory effect on hepatitis B virus by suppression of manganese superoxide dismutase expression. The FEBS Journal, 276: 2599-2614. doi:10.1111/j.1742-4658.2009.06988.x

9. Tang, Jing-jie, et al. “Inhibition of SREBP by a Small Molecule, Betulin, Improves Hyperlipidemia and Insulin Resistance and Reduces Atherosclerotic Plaques.” Cell Metabolism, vol. 13, no. 1, 2011, pp. 44–56., https://doi.org/10.1016/j.cmet.2010.12.004

10. Ehrlich, Avner and Uhl, Skyler and Ioannidis, Konstantinos and Hofree, Matan and tenOever, Benjamin R. and Nahmias, Yaakov, The SARS-CoV-2 Transcriptional Metabolic Signature in Lung Epithelium. Available at SSRN: https://ssrn.com/abstract=3650499 or http://dx.doi.org/10.2139/ssrn.3650499

11. Yuan, S., Chu, H., Chan, J. F., Ye, Z. W., Wen, L., Yan, B., Lai, P. M., Tee, K. M., Huang, J., Chen, D., Li, C., Zhao, X., Yang, D., Chiu, M. C., Yip, C., Poon, V. K., Chan, C. C., Sze, K. H., Zhou, J., Chan, I. H., … Yuen, K. Y. (2019). SREBP-dependent lipidomic reprogramming as a broad-spectrum antiviral target. Nature communications, 10(1), 120. https://doi.org/10.1038/s41467-018-08015-x

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