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. {module INSIDE STORY}

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 spike’s 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 Bristol’s School of Chemistry, 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.”

Alison Derbenwick Miller, Vice President, Oracle for Research, said: “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 team included experts from Bristol UNCOVER Group, including Bristol’s Schools of Chemistry, Biochemistry, Cellular and Molecular Medicine, and Max Planck Bristol Centre for Minimal Biology, and Bristol Synthetic Biology Centre, using Bristol’s high performance computers and the UK supercomputer, ARCHER, as well as Oracle cloud supercomputing. The study was supported by grants from the EPSRC 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’ by C Toelzer et al in Angewandte Chemie.

Science "Viewpoint" article stresses importance of sequencing data to control COVID-19 pandemic

The emergence of SARS-CoV-2 virus variants that are adding twists in the battle against COVID-19 highlight the need for better genomic monitoring of the virus, says Katia Koelle, associate professor of biology at Emory University.

"Improved genomic surveillance of SARS-CoV-2 across states would really help us to better understand how the virus causing the pandemic is evolving and spreading in the United States," Koelle says. "More federal funding is needed, along with centralized standards for sample collection and genetic sequencing. Researchers need access to such metadata to better track how the virus is spreading geographically, and to identify any new variants that may make it harder to control, so that health officials can respond more quickly and effectively." {module INSIDE STORY}

Koelle studies the interplay between viral evolution and the epidemiological spread of viral infectious diseases. She is senior author of a "Viewpoint" article just published in the journal Science on the importance of SARS-CoV-2 sequencing to control the COVID-19 pandemic.

Michael Martin, a PhD student in Emory's Population, Biology and Ecology Program and a member of Koelle's lab, is first author of the Science article. David VanInsberghe, a post-doctoral fellow in Koelle's lab, is co-author.

"Research into SARS-CoV-2 has been going at lightning speed," Martin says. "This acceleration has provided us with one of the largest datasets ever so quickly assembled for a disease. We've learned a lot so far about how this virus spreads and adapts, but we still have many blind spots that need to be addressed."

The article summarizes key insights about SARS-CoV-2 that have already been gained by sequencing of its genome from individual patient samples. It also cites challenges that remain, including the collection and integration of metadata into genetic analyses and the need for the development of more efficient and scalable computational methods to apply to hundreds of thousands of genomes.

A genome is an organism's genetic material. Human genomes are made up of double-stranded DNA, coded in four different nucleotide base letters. A single human genome consists of more than 3 billion base pairs. In contrast, the genome of coronaviruses, including SARS-CoV-2, are made of RNA, which can have a simpler structure than DNA. The SARS-CoV-2 genome, for instance, consists of a single RNA strand that is only 30,000 letters long. Sequencing is a technique that provides a read-out of these letters.

If the SARS-CoV-2 virus is found in a sample swabbed from someone's nose or mouth, it confirms the likelihood that the person is carrying the virus, whether they have symptoms of COVID-19 or not. The virus in the sample can also be sequenced.

"Sequencing the virus is like fingerprinting it," Koelle explains. "And based on how close the fingerprints match between samples -- that is, how close they are genetically -- you can at times learn who is infecting whom. Analyzing sequences from samples taken from infected individuals in a given region over time can provide even more information."

Analyses of SARS-CoV-2 sequencing data have enabled researchers to estimate the timing of SARS-CoV-2 spillover into humans; identify some of the transmission routes in its global spread; determine infection rates and how they change within a region; and identify the emergence of some new variants of concern.

Viral genomes can mutate during replication, changing letters as they spread to new people. Most of these random mutations will likely not affect the transmissibility or virulence of a virus -- but a few may make it even more difficult to fight. Early evidence, for instance, suggests that a SARS-CoV-2 variant that recently emerged in the UK may be more easily transmitted and potentially more severe. A South African variant shows signs that it may reduce the efficacy of existing vaccines, while a variant first detected in Brazil also contains mutations that health officials worry may make the virus spread more quickly.

"It can be difficult to identify which variants actually change how the virus replicates, spreads and causes disease because of confounding factors," Martin explains. "If a variant spreads more quickly, for instance, you have to tease apart whether that was due to it becoming more transmissible or if someone who was infected with it attended a large gathering."

The better data researchers have, the faster they can solve such puzzles, he adds.

Technological advances during recent years have made it more efficient and less costly to generate sequencing data. Barely a year after it emerged, more than 400,000 sequences of SARS-CoV-2 are now available in public databases, such as the GISAID platform which was launched in 2008 to share information among National Influenza Centers for the WHO Global Influenza Surveillance and Response System.

"A large chunk of the public sequencing data for SARS-CoV-2 has come out of the UK," Koelle notes. "That's because the British government has an initiative to do high-density sampling of the SARS-CoV-2 genome."

The rich data set from the UK helped identify the emergence of the variant in Britain that is spreading rapidly. "There might be other variants of concern emerging in other places around the world besides the ones already identified, but we just don't know because we don't have as good of surveillance in those locations," Koelle says.

"While the United States has been slow in efforts to sequence SARS-CoV-2 from samples across the nation, there are several excellent viral sequencing efforts and phylogenetic analyses, primarily driven by academic researchers, that have helped to understand SARS-CoV-2 transmission more locally," Koelle says. "We have the expertise in the U.S., but the effort is more piecemeal."

"We need a coordinated, nationally standardized program to do widespread sequencing of SARS-CoV-2 in the United States," Martin says. "Much of the data collected now just has a state identifier but we need greater resolution while also protecting patient privacy. More county-level identifiers, for instance, would be one way to greatly improve the quality and the depth of the data."

Once the COVID-19 pandemic ebbs, it's important to continue to build the national infrastructure and systems for infectious disease surveillance -- including viral sequencing -- and to keep it in place, both researchers stress.

"There will be more infectious disease pandemics, and we need to be better prepared," Martin says.