University Of Bristol Study Shows That Vitamins, Steroids and Retinoids Can Help As Adjuvants To Treat COVID-19

Vitamins, steroids and retinoids can be used as adjuvants to treat COVID-19 according to a new study by scientists from the University of Bristol.


 
According to the study abstract, “The study team investigated the binding of linoleate and other potential ligands to the recently discovered fatty acid binding site in the SARS-CoV-2 spike protein by using docking and molecular dynamics simulations. Simulations suggest that linoleate and dexamethasone stabilize the locked spike conformation, thus reducing the opportunity for ACE2 interaction. In contrast, cholesterol may expose the receptor-binding domain by destabilizing the closed structure, preferentially binding to a different site in the hinge region of the open structure. The study docked a library of FDA-approved drugs to the fatty acid site using an approach that reproduces the structure of the linoleate complex. Docking identifies steroids (including dexamethasone and vitamin D); retinoids (some known to be active in vitro, and vitamin A); and vitamin K as potential ligands that may stabilize the closed conformation. The SARS-CoV-2 spike fatty acid site may bind a diverse array of ligands, including dietary components, and therefore provides a promising target for therapeutics or prophylaxis.”
 
The study findings were published in the peer reviewed journal of the German Chemical Society, Angewandte Chemie. https://onlinelibrary.wiley.com/doi/epdf/10.1002/anie.202015639
 
New evidence is emerging that vitamin D and possibly vitamins K and A might help combat COVID-19. Mano of these vitamins, steroids and retinoids can be incorporated into COVID-19 treatment protocols as adjuvants.
 
This new research indicates that these dietary supplements and compounds could bind to the viral spike protein and so might reduce SARS-CoV-2 infectivity.
 
Importantly in contrast, cholesterol may increase infectivity, which could explain why having high cholesterol is considered a risk factor for serious disease.
 
The study team showed that linoleic acid binds to a specific site in the viral spike protein, and that by doing so, it locks the spike into a closed, less infective form.
 
The research team used computational methods to search for other compounds that might have the same effect, as potential treatments.
 
The study team hoped to prevent human cells becoming infected by preventing the viral spike protein from opening enough to interact with a human protein (ACE2).
 
Typically new anti-viral drugs can take years to design, develop and test, so the researchers looked through a library of approved drugs and vitamins to identify those which might bind to this recently discovered 'druggable pocket' inside the SARS-CoV-2 spike protein.
 
The study team first studied the effects of linoleic acid on the spike, using computational simulations to show that it stabilizes the closed form. Further simulations showed that dexamethasone which is an effective treatment for COVID-19 might also bind to this site and help reduce viral infectivity in addition to its effects on the human immune system.
 
The researchers from the University of Bristol then con ducted simulations to see which other compounds bind to the fatty acid site.
 
They identified some drugs that have been found by experiments to be active against the virus, suggesting that this may be one mechanism by which they prevent viral replication such as, by locking the spike structure in the same way as linoleic acid.
 
The study findings suggested several drug candidates among available pharmaceuticals and dietary components, including some that have been found to slow SARS-CoV-2 reproduction in the laboratory. These have the potential to bind to the SARS-CoV-2 spike protein and may help to prevent cell entry.
 
The computational simulations also predicted that the fat-soluble vitamins D, K and A bind to the spike in the same way making the spike less able to infect cells.
 
Co-researcher Dr Deborah Shoemark, Senior Research Associate (Biomolecular Modelling) in the School of Biochemistry-University of Bristol explained to Thailand Medical News, ”Our findings help explain how some vitamins may play a more direct role in combatting COVID than their conventional support of the human immune system.”
 
She further added, “Obesity is a major risk factor for severe COVID. Vitamin D is fat soluble and tends to accumulate in fatty tissue. This can lower the amount of vitamin D available to obese individuals. Countries in which some of these vitamin deficiencies are more common have also suffered badly during the course of the pandemic. Our research suggests that some essential vitamins and fatty acids including linoleic acid may contribute to impeding the spike/ACE2 interaction. Deficiency in any one of them may make it easier for the virus to infect."
 
It has been known that pre-existing high cholesterol levels have been associated with increased risk for severe COVID-19. https://www.biorxiv.org/content/10.1101/2020.05.09.086249v3
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340589/
 
Studies that the SARS-CoV-2 spike protein binds cholesterol led the team to investigate whether it could bind at the fatty acid binding site. https://www.medrxiv.org/content/10.1101/2020.04.16.20068528v3
 
The study team’s simulations indicate that it could bind, but that it may have a destabilizing effect on the spike's locked conformation, and favour the open, more infective conformation.
 
Corresponding author Professor Dr Adrian Mulholland, of Bristol's School of Chemistry commented, "We know that the use of cholesterol lowering statins reduces the risk of developing severe COVID and shortens recovery time in less severe cases. Whether cholesterol de-stabilizes the ‘benign’, closed conformation or not, our results suggest that by directly interacting with the spike, the virus could sequester cholesterol to achieve the local concentrations required to facilitate cell entry and this may also account for the observed loss of circulating cholesterol post infection."
 
He further added, "Our simulations show how some molecules binding at the linoleic acid site affect the spike's dynamics and lock it closed. They also show that drugs and vitamins active against the virus may work in the same way. Targeting this site may be a route to new anti-viral drugs. A next step would be to look at effects of dietary supplements and test viral replication in cells."
 
Vice President, Oracle for Research, Alison Derbenwick Miller added, “It's incredibly exciting that researchers are gaining new insights into how SARS-CoV-2 interacts with human cells, which ultimately will lead to new ways to fight COVID-19. We are delighted that Oracle's high-performance cloud infrastructure is helping to advance this kind of world-changing research. Growing a globally-connected community of cloud-powered researchers is exactly what Oracle for Research is designed to do."
 
The study team concluded, “Docking suggests that some compounds that are known to be active against SARS-CoV-2 may bind at the Fatty Acid (FA) site of the spike. Docking also identifies vitamins A, D and K as potential ligands for the spike FA site. Further study is warranted to explore whether fat soluble vitamins play a direct role in protecting against SARS-CoV-2 infection, e.g. by stabilizing the locked spike conformation. In addition to vitamin A, three retinoids that are known inhibitors of SARS-CoV-2 replication are predicted to bind at the FA site. Docking also suggests that the FA pocket may bind a range of natural and synthetic steroids. These findings suggest that, in addition to their effects on host response, certain vitamins, retinoids and steroids may also affect SARS-CoV-2 by binding to the spike protein. This is worthy of further investigation.”
 
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