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Pocket feature shared by deadly coronaviruses could lead to pan-coronavirus antiviral treatment

Spike glycoprotein structure of SARS-CoV, the coronavirus causing the 2002 outbreak. When linoleic acid is bound, the structure is locked in a non-infectious form

Spike glycoprotein structure of SARS-CoV, the coronavirus causing the 2002 outbreak. When linoleic acid is bound, the structure is locked in a non-infectious form. The cryo-EM density, calculated by cloud computing, is shown (left) along with the protein structure (middle). Linoleic acid molecules are coloured in orange. A zoom-in of the pocket (boxed), conserved in all deadly coronaviruses, is shown Christiane Schaffitzel and Christine Toelzer, University of Bristol

Press release issued: 23 November 2022

Scientists have discovered why some coronaviruses are more likely to cause severe disease, which has remained a mystery, until now. Researchers of the University of Bristol-led study, published in Science Advances today [23 November], say their findings could lead to the development of a pan-coronavirus treatment to defeat all coronaviruses—from the 2002 SARS-CoV outbreak to Omicron, the current variant of SARS-CoV-2, as well as dangerous variants that may emerge in future.

In this new study, an international team, led by Bristol's Professor Christiane Schaffitzel, scrutinised the spike glycoproteins decorating all coronaviruses. They reveal that a tailor-made pocket feature in the SARS-CoV-2 spike protein, first discovered in 2020, is present in all deadly coronaviruses, including MERS and Omicron. In striking contrast, the pocket feature is not present in coronaviruses which cause mild infection with cold-like symptoms.

The team say their findings suggest that the pocket, which binds a small molecule, linoleic acid—an essential fatty acid indispensable for many cellular functions including inflammation and maintaining cell membranes in the lungs so that we can breathe properly—could now be exploited to treat all deadly coronaviruses, at the same time rendering them vulnerable to a linoleic acid-based treatment targeting this pocket.   

COVID-19, caused by SARS-CoV-2, is the third deadliest coronavirus outbreak following SARS-CoV in 2002 and MERS-CoV in 2012. The much more infectious SARS-CoV-2 continues to infect people and damage communities and economies worldwide, with new variants of concern emerging successively, and Omicron evading vaccination and immune response.

Professor Schaffitzel from Bristol's School of Biochemistry, explained: "In our earlier work we identified the presence of a small molecule, linoleic acid, buried in a tailor-made pocket within the SARS-Cov-2 glycoprotein, known as the 'Spike protein', which binds to the human cell surface, allowing the virus to penetrate the cells and start replicating, causing widespread damage.

"We showed that binding linoleic acid in the pocket could stop virus infectivity, suggesting an anti-viral treatment. This was in the original Wuhan strain that started the pandemic. Since then, a whole range of dangerous SARS-CoV-2 variants have emerged, including Omicron, the currently dominating variant of concern. We scrutinised every new variant of concern and asked whether the pocket function is still present."

Omicron has undergone many mutations, enabling it to escape immune protection offered by vaccination or antibody treatments that lag behind this rapidly evolving virus.  Intriguingly, while everything else may have changed, the researchers found that the pocket remained virtually unaltered, also in Omicron.

Christine Toelzer, Research Associate in the School of Biochemistry and lead author of the study, added: "When we realised that the pocket we had discovered remained unchanged, we looked back and asked whether SARS-CoV and MERS-CoV, two other deadly coronaviruses causing previous outbreaks years ago, also contained this linoleic acid binding pocket feature." 

The team applied high-resolution electron cryo-microscopy, cutting-edge computational approaches and cloud computing. Their results showed that SARS-CoV and MERS-CoV also had the pocket, and could bind the ligand, linoleic acid, by a virtually identical mechanism.  

Professor Schaffitzel concluded: "In our current study, we provide evidence that the pocket remained the same in all deadly coronaviruses, from the first SARS-CoV outbreak 20 years ago to Omicron today. We have shown previously that linoleic acid binding to this pocket induces a locked spike, abrogating viral infectivity. We also show now that linoleic acid supplementation suppresses virus replication inside cells. We anticipate that future variants will also contain the pocket, which we can exploit to defeat the virus."

Halo Therapeutics, a recent University of Bristol spin-out Professor Schaffitzel co-founded, is using these findings to develop pocket-binding pan-coronavirus antivirals.

The team included experts from the Bristol UNCOVER Group, Max Planck Bristol Centre for Minimal Biology, Bristol University spin-out Halo Therapeutics Ltd, and collaborators in Sweden and France. The studies have been supported by funds from Max Planck Gesellschaft, Wellcome Trust and European Research Council, with additional support from Oracle for Research for high-performance cloud computing resources.

Paper

'The free fatty acid-binding pocket is a conserved hallmark in pathogenic b-coronavirus spike proteins from SARS-CoV to Omicron' by C Toelzer et al. in Science Advances

Further information

About Professor Christiane Schaffitzel
Christiane Schaffitzel is also Academic Lead of the BBSRC/Wellcome Trust GW4 Cryo-EM Facility at Bristol, Wellcome Trust Investigator, Coordinator of the European Innovation Council ADDovenom consortium to develop new snakebite treatments, and CTO of Halo Therapeutics Ltd.

Study collaborators at University of Bristol
University of Bristol collaborators on the project include Professor Paul Verkade and his team in the School of Biochemistry and Professor Andrew Davidson and his team in the School of Cellular and Molecular Medicine who carried out correlated light and electron microscopy experiments.

About coronavirus (SARS-CoV-2)
The surface of the coronavirus particle has proteins 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. Three deadly coronavirus outbreaks occurred to date, SARS-CoV in 2002, MERS-CoV in 2013 remaining endemic in the Middle East, and SARS-CoV-2 causing the global pandemic in 2019.

Bristol UNCOVER Group
In 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: @BristolUncover

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

Find out how you can support their critical work.

Bristol UNCOVER is supported by the Elizabeth Blackwell Institute
Find out more about the Institute’s 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 the Max Planck Bristol Centre
The Max Planck Bristol Centre (MPBC) is a joint research centre of the Max Planck Society and the University of Bristol. The MPBC is focused on the field of synthetic and minimal biology. Located in Bristol and with nodes at Max Planck Institutes in Martinsried, Mainz and Heidelberg, scientists in the MPBC aim to construct artificial cells, cytoskeletons and nanoscale molecular machines to investigate the building blocks necessary for life and their applications.

Follow us on Twitter: @MaxPlanckBris

About Halo Therapeutics Ltd
Halo Therapeutics is a University of Bristol spin-out developing safe, self-administered pan-coronavirus prophylactics and early antiviral treatments. Halo Therapeutics Ltd is located at Unit Dx, S. Philips Central, Albert Road, Bristol, UK.

About Oracle for Research
Oracle for Research is a global community that is working to address complex problems and drive meaningful change in the world. The program provides scientists, researchers, and university innovators with high-value, cost-effective Cloud technologies, participation in Oracle research user community, and access to Oracle’s technical support network. Through the program’s free cloud credits, users can leverage Oracle’s proven technology and infrastructure while keeping research-developed IP private and secure.

Learn more at Oracle for Research and Twitter: @OracleResearch

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