Research examines how vitamins, steroids, and antivirals affect COVID-19

New research from the University of Bristol found that dietary supplements and compound, including vitamins A, D, and K, could bind to the viral spike protein and reduce the virus that causes the novel coronavirus (COVID-19), SARS-CoV-2, infectivity. In contrast, cholesterol may increase infectivity, which could explain why having high cholesterol is considered a risk factor for serious disease, according to the study published in the journal of the German Chemical Society Angewandte Chemie.

Recently, researchers showed that linoleic acid binds to a specific site in the viral spike protein, and that by doingso, it locks the spike into a closed, less infective form. For the current study, the research team used computational methods to search for other compounds that might have the same effect, as potential treatments. They said they hope to prevent human cells becoming infected by preventing the viral spike protein from opening enough to interact with a human protein (ACE2). 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 that might bind to this recently discovered druggable pocket inside the SARS-CoV-2 spike protein, according to the study.

The researchers 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 a 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 team then conducted simulations to see which other compounds bind to the fatty acid site. This 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 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 simulations also predicted that the fat-soluble vitamins A, D, and A bind to the spike in the same way making the spike less able to infect cells, according to the study.

" Our findings help explain how some vitamins may play a more direct role in combatting [COVID-19] than their conventional support of the human immune system,” said Deborah Shoemark, BSc, PhD, senior research associate who modelled the spike, in a statement. “Obesity is a major risk factor for severe COVID-19. 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."

Additionally, pre-existing high cholesterol levels have been associated with increased risk for severe COVID-19. Reports that the SARS-CoV-2 spike protein binds cholesterol led the team to investigate whether it could bind at the fatty acid binding site. The simulations indicate that it could bind, but that it may have a destabilizing effect on the spike's locked conformation, and favor the open, more infective conformation, the researchers said.

"We know that the use of cholesterol lowering statins reduces the risk of developing severe COVID and shortens recovery time in less severe cases,” said Shoemark. “Whether cholesterol destabilizes 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."

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