Evidence is emerging that vitamin D and possibly vitamins K and A might help combat COVID-19. A new study from the University of Bristol published in the journal of the German Chemical Society Angewandte Chemie has shown how they and other antiviral drugs might work. The research indicates that these dietary supplements and compounds could bind to the viral spike protein and so might reduce 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.

Recently, Bristol researchers 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. Now, a research team has used computational methods to search for other compounds that might have the same effect, as potential treatments. 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 which might bind to this recently discovered druggable pocket inside the SARS-CoV-2 spike protein.

The 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 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 D, K and A bind to the spike in the same way making the spike less able to infect cells.

Dr Deborah Shoemark, Senior Research Associate (Biomolecular Modelling) in the School of Biochemistry, who modelled the spike, explained: 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.

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.

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. Their simulations indicate that it could bind, but that it may have a destabilising effect on the spikes locked conformation, and favour the open, more infective conformation.

Dr Shoemark continued: 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-stabilises 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.

Professor Adrian Mulholland, of Bristols School of Chemistry, added: Our simulations show how some molecules binding at the linoleic acid site affect the spikes 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.

Alison Derbenwick Miller, Vice President, Oracle for Research, said: Its 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 Oracles 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 team included experts fromBristol UNCOVER Group, including Bristols Schools of Chemistry, Biochemistry, Cellular and Molecular Medicine, and Max Planck Bristol Centre for Minimal Biology, and BrisSynBio, using Bristols high performance computers and the UK supercomputer, ARCHER, as well as Oracle cloud computing. The study was supported by grants from theEPSRC and the BBSRC.

Paper

'Molecular simulations suggest vitamins, retinoids and steroids as ligands binding the free fatty acid pocket of SARS-CoV-2 spike protein' byDeborah Karen Shoemark, Charlotte K. Colenso, Christine Toelzer, Kapil Gupta, Richard B. Sessions, Andrew D. Davidson, Imre Berger, Christiane Schaffitzel, James SpencerandAdrian J. Mulhollandin Angewandte Chemie

About coronavirus (SARS-CoV-2)The surface of the coronavirus particle has proteins sticking out of it known as Spike proteins which are embedded in a membrane. They have the appearance of tiny little crowns, giving the virus its name (corona). Inside the membrane is the viral genome wrapped up in other proteins. The genome contains all the genetic instruction to mass produce the virus. Once the virus attaches to the outside of a human cell, its membrane fuses with the human cell membrane and its genetic information into the human cell. Next, the virus instructs the cell to start replicating its genome and produce its proteins. These are then assembled into many new copies of the virus which, upon release, can infect many more cells. The viral proteins play diverse further roles in coronavirus pathology.

Support our COVID-19 researchBristols researchers are part of a global network of scientists responding urgently to the challenge of the coronavirus pandemic.

Find out how you can support their critical work.

Bristol UNCOVER GroupIn response to the COVID-19 crisis, researchers at the University of Bristol formed the Bristol COVID Emergency Research Group (UNCOVER) to pool resources, capacities and research efforts to combat this infection.

Bristol UNCOVER includes clinicians, immunologists, virologists, synthetic biologists, aerosol scientists, epidemiologists and mathematical modellers and has links to behavioural and social scientists, ethicists and lawyers.

Follow Bristol UNCOVER on Twitter at: twitter.com/BristolUncover

For more information about the University of Bristols coronavirus (COVID-19) research priorities visit: http://www.bristol.ac.uk/research/impact/coronavirus/research-priorities/

Bristol UNCOVER is supported by the Elizabeth Blackwell InstituteFind out more about the Institutes COVID-19 research looking into five key areas: virus natural history, therapeutics and diagnostics research; epidemiology; clinical management; vaccines; and ethics and social science.

About Bristol BioDesign InstituteBristol BioDesign Institute (BBI)is the University of Bristol's Specialist Research Institute for synthetic biology. With wide-ranging applications from health to food security, BBI combines pioneering synthetic biology approaches with understanding biomolecular systems to deliver the rational design and engineering of biological systems for useful purposes.

This is delivered through multidisciplinary research that brings together postgraduate and postdoctoral researchers, academics, policy makers and industry, whilst also engaging the public with emerging solutions to global challenges.

About BrisSynBio, a BBSRC/ EPSRC-funded Synthetic Biology Research CentreBrisSynBiois a multi-disciplinary research centre that focuses on the biomolecular design and engineering aspects of synthetic biology.

BrisSynBio is part of theBristol BioDesign Institute.

Our overarching aims are to:

About Oracle for Research

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