BREAKING! COVID-19 Phytochemicals: Furin Inhibition May Lower Risk Of COVID Severity, Berberine, A HIF-1 Inhibitor Derived From Plants Could Help

COVID-19 Phytochemicals: A new research by scientist Dr Kara Fitzgerald from the Institute for Functional Medicine-Washington has revealed that furin Inhibition may lower risk of COVID severity. The study also advocates the use of furin inhibitors including heparin and a more so Berberine, a HIF-1 Inhibitor derived from plants.


The Barberry Plant
 
Berberine is a phytochemical that is a quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids found in several plants including European barberry, goldenseal, goldthread, Oregon grape, phellodendron, and tree turmeric. Berberine is usually found in the roots, rhizomes, stems, and bark. Berberine is most commonly taken by mouth for diabetes, high levels of cholesterol or other fats (lipids) in the blood (hyperlipidemia), and high blood pressure.
 
According to the researcher, furin is a protease that is ubiquitous in mammalian metabolism. One of the innovations that make the SARS-CoV-2 more infectious than its ancestor viruses is the addition of a furin cleavage site. Conditions associated with elevated furin levels, including diabetes, obesity, and hypertension, overlap greatly with vulnerability to the severe form of COVID-19. The study team suggests that diet and lifestyle modifications that reduce the associated comorbidities may prevent the development of severe COVID-19 by, in part, lowering circulating furin levels. Likewise, natural and pharmaceutical inhibitors of furin may be candidate prophylactic interventions or, if used early in the COVID-19, may prevent the development of critical symptoms.
 
The study findings were published in the peer reviewed journal: The Permanente Journal. https://www.thepermanentejournal.org/issues/2020/summer/7533-furin-protease-from-sars-cov-2-to-anthrax,-diabetes,-and-hypertension.html#ref
 
The SARS-CoV-2 virus, the infectious agent that causes COVID-19, broke out in December 2019 and is still spreading rapidly. The World Health Organization (WHO) and other major national and international public health bodies have branded the virus's spread as a worldwide pandemic, with over 62.4 million individuals infected and over 1.46 million deceased.
While the global health crisis evolves, and is expected to further worsen, scientists have been racing to provide insight into the virus structure to find a therapeutic target that can mitigate its impact on those with severe cases.
 
Dr Fitzgerald, has explained the role of furin protease in developing severe COVID-19 illness. Conditions tied to elevated furin levels including obesity, hypertension, and diabetes show overlap with vulnerability to more severe forms of COVID-19.
 
Typically proteases describe a large group of diverse hydrolytic enzymes. They catalyze proteolysis, the breakdown of proteins into smaller polypeptides or single amino acids.
 
Importantly proteases also play pivotal roles in the biochemical and physiological processes throughout the body.
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The protease furin, which was officially identified in 1990, catalyzes a simple biochemical reaction ie the proteolytic maturation of proprotein substrates in the secretory pathway. The protease has an important role in homeostasis, as well as diseases ranging from Alzheimer's disease and anthrax to Ebola fever, cancer, diabetes, obesity, and hypertension.

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The Coronaviruses (CoVs) contains four structural proteins, including the Spike (S), Membrane (M), Envelope (E), and Nucleocapsid (N). The Spike protein, a trimeric glycoprotein of coronaviruses, mediates the coronaviruses' binding to the host cell's surface-specific receptors.
 
The S or Spike protein plays a key role in the early stages of viral infection, with the S1 domain responsible for receptor binding. Meanwhile, the S2 domain mediates membrane fusion.
 
Importantly the S glycoprotein must be cleaved by cell proteases to enable exposure of the fusion sequences, which is needed for cellular entry. The nature of cell proteases that cleave the S glycoprotein differs according to the type of coronavirus.
 
In the case of the severe acute respiratory syndrome coronavirus (SARS-CoV), S glycoprotein is uncleaved upon virus release from cells but is likely cleaved during virus entry into a cell. This is the agent that was responsible for the SARS outbreak that occurred in China in 2002.
 
Contrastingly, the Middle East respiratory syndrome coronavirus (MERS-CoV), S glycoprotein contains a furin cleavage site and is processed by the intracellular proteases upon exit from the cell. The MERS outbreak emerged in Saudi Arabia in 2012.
 
However the Spike glycoprotein of the newly emerged SARS-CoV-2 ,the causative pathogen for COVID-19 contains a furin cleavage complex (FCC). The modified S glycoprotein can interact with the cell surface receptor angiotensin-converting enzyme 2 (ACE2), which is the specific receptor found in human cells, particularly epithelium, that the virus utilizes to gain entry. The S1 or receptor-binding domain contacts with ACE2, which is facilitated by a furin cleavage.
 
Research has shown that the S protein of SARS-CoV-2 is between 10 and 20 times more likely to bind to human ACE2 than the S protein of previous coronaviruses. This means that SAR-CoV-2 is significantly more infectious than both SARS and MERS. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7114094/
 
Importantly Dr Fitzgerald noted that SARS-CoV-2 uses endogenous furin to cleave the S protein in the trans-Golgi network right after virion assembly. The mechanism separates furin from other virally hijacked proteases, which may increase the pathogenicity of SARS-CoV-2. https://chinaxiv.org/abs/202002.00062
 
Also the presence of the FCC allows the SARS-CoV-2 coronavirus to spread systematically and cause higher rates of severe disease and death. Furin is present in most tissues and is highly expressed in the lungs, which may explain how the virus gains entry into the respiratory tract and causes infection.
 
The research explored how the potential that baseline inflammation contributes to a delayed response from the immune system. Also, furin may hold the key to a better understanding of why there are virus-initiated immune responses and an influence of comorbidities on COVID-19 severity.
 
America has been overwhelmed with the spread of SARS-CoV-2. More than 1 in 3 Americans are also thought to have cardiometabolic diseases, which are known as comorbidities to COVID-19.
https://www.cdc.gov/diabetes/library/features/diabetes-stat-report.html#:~:text=88%20million%20American%20adults%E2%80%94approximately%201%20in%203%E2%80%94have%20prediabetes.
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175079/
 
https://pubmed.ncbi.nlm.nih.gov/32216698/
 
The study team noted that the presence of elevated furin levels seen in this population makes them vulnerable to SARS-CoV-2 entry and replication. They are more susceptible to being infected with SARS-CoV-2 and more likely to experience severe complications as it spreads rapidly throughout the body.
 
In addition, furin activates several peptides that may drive the development of COVID-19 disease. First, furin facilitates the renin-angiotensin-aldosterone system (RAAS) by stimulating the prorenin receptor. As a result, vasoconstrictor angiotensin is formed, and aldosterone is secreted, which can cause hypokalemia. https://pubmed.ncbi.nlm.nih.gov/30706700/
 
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2767008
 
Importantly Hypokalemia and RAAS interference through ACE2 are seen in COVID-19. https://www.thailandmedical.news/news/covid-19-research-updates-chinese-study-reveals-that-hypokalemia-present-in-almost-all-covid-19-patients
 
Certain COVID-19 patients experience coagulopathy and hypoxia, which involves the clotting factor VIII and the von Willebrand factor. Furin is needed in the activation of the clotting factor VIII.
 
Interestingly all these mechanisms contribute to developing severe symptoms of COVID-19. Severe hypoxia being a hallmark finding in severe COVID- 19 cases.
 
Hence furin may therefore act as a therapeutic target for COVID-19 treatment. furin inhibition may help in treating severely ill patients.
 
The anticoagulating agent heparin is a furin inhibitor and has an accepted risk-benefit ratio. Since some patients with severe COVID-19 experience the risk of coagulopathy, heparin use has been linked to lower mortality in hospitalized patients.
 
Importantly, hypoxia induces furin expression as well as all 3 FUR gene promoters harbor binding sites for hypoxia-inducible factor-1 (HIF-1).
 
It was found that Berberine, which is an HIF-1 inhibitor, maybe a potential treatment for COVID-19 patients.
 
Berberine is a bioactive compound that can be extracted from several different plants, including a group of shrubs called Berberis. Technically, it belongs to a class of compounds called alkaloids. It has a yellow color, and has often been used as a dye.
 
Berberine has a long history of use in traditional Chinese medicine, where it was used to treat various ailments. Now, modern science has confirmed that it has impressive benefits for several different health problems. https://pubmed.ncbi.nlm.nih.gov/22842630/
 
However, one of the main actions of berberine is to activate an enzyme inside cells called AMP-activated protein kinase (AMPK) .This enzyme is sometimes referred to as a “metabolic master switch” It is found in the cells of various organs, including the brain, muscle, kidney, heart and liver. This enzyme plays a major role in regulating metabolism.
https://diabetes.diabetesjournals.org/content/55/8/2256.full
 
https://pubmed.ncbi.nlm.nih.gov/10409121/
 
Berberine also affects various other molecules inside cells, and may even affect which genes are turned on or off. https://pubmed.ncbi.nlm.nih.gov/24174332/
 
Berberine has also been used in treating other viral infections.
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977228/
 
https://pubmed.ncbi.nlm.nih.gov/20161729/
 
https://amb-express.springeropen.com/articles/10.1186/s13568-020-01088-2
 
Berberine is also one of the many phytochemicals and herbs used in Thailand Medical News Therapeutic Teas to treat COVID-19 and also as a prophylactic against the SARS-CoV-2. https://www.thailandmedical.news/news/new-therapeutic-teas-
 
Just as important, lifestyle modification among high-risk patients and those with comorbidities may help reduce furin levels and baseline inflammation. Maintaining a healthy weight and lifestyle can hamper viral entry and replication.
 
Dr Fitzgerald told Thailand Medical News, "Addressing comorbidities and associated elevated furin levels through diet, lifestyle modifications, and pharmacologic management is a logical strategy for reducing COVID-19 pathogenicity. Natural and pharmacologic furin inhibitors may prove highly useful to inhibit viral entry and propagation.”
 
He added, “Importantly the relatively cheap and non-toxic plant phytochemical Berberine should be further studied as a potential therapeutic agent to treat severe COVID-19.”
 
For more on COVID-19 Phytochemicals, keep on logging to Thailand Medical News.

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