Find out more about Diamond's response to virus research.
This animation shows how the SARS-CoV-2 virus infection mechanism works at the cellular level, revealing unseen pathways of the virus assembly and egress, and the cellular structural changes caused by the virus.
Just over a year ago, little was known about the virus, how it worked to infect us and how it was passed on. Now in our third lockdown we have all had to adapt to living and working alongside it. Oxfordshire scientists and other global experts, often in collaboration with Diamond and many on Oxford’s Harwell Science & Innovation Campus, have been able in record time, to unlock some of the virus’s secrets. They have made huge progress in understanding how COVID-19 operates and as a result, have opened the doors to real possibilities of solutions and therapies.
Professor Sir David Stuart, Life Sciences Director at Diamond and Joint head of Structural Biology at the University of Oxford, explains:
Structural understanding of the viral components is key to the discovery of therapeutics and so far work has concentrated on the spike protein, the main protease, RNA polymerase and other non-structural proteins, as well as the spike interactions with host receptor ACE2 and neutralising antibodies, using a range of tools from synchrotron based X-ray crystallography to cryoEM (Electron Microscopy) and cryoET (Electron Tomography).
At the beginning of the pandemic we didn’t know exactly what the virus looked like but in record time, it has been dissected in great detail. This is really important because by understanding how it works and mapping out the infection mechanism, we are much closer to our goal of finding therapies and also finding alternative targets to the spike protein, as its rapid mutations threaten the effectiveness of current vaccines and antibody therapies.
The many COVID-19 related research projects that Diamond is working on are a great demonstration of the powerful synergy between Diamond and its neighbouring research institutes, the Research Complex at Harwell and the Rosalind Franklin Institute. Diamond is working with its valued users and many partners to look at the fundamental interactions of the virus, from which it is hoped new therapies can be developed. Over 60 projects have received attention, enabling the study of how existing drugs, that have already been tested and approved for other diseases, can be repurposed and used to treat patients. The array of specialised tools and instruments at Diamond, along with the scientific and technical expertise of its staff, allow for many different techniques to be used, from looking at the structure of the virus and fitting drugs into it, like a tiny jigsaw puzzle, to taking direct images of the virus without its infectious component, making it possible to see how it interacts with drugs.
19 April 2021 - Science is keeping us one step ahead of Covid mutations.
The possibility of escape from natural and vaccine-induced immunity against the SARS CoV-2 virus has prompted a rush to understand the consequences of these changes and to develop new vaccine constructs tailored to the variants. Three major new science papers, published in the journal, Cell on 19 April provide valuable new information about how previously infected or vaccinated individuals respond to these new variants and antibodies. Their conclusions indicate that even if antibody responses to the new variants are compromised, they are likely to provide some protection. In addition, T cell responses to the virus spike may not be disrupted by the mutational changes and should be able to limit spread to the lower respiratory tract and prevent severe disease.
The first paper ‘Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera’ examines how the UK ‘Kent’ variant responded to antibodies from patients who had been infected by the original coronavirus as well as people who had received either an Oxford-AstraZeneca or a Pfizer vaccine. Using X-ray crystallography at Diamond Light Source, they discovered how the single mutation in the receptor binding domain of the spike protein interferes with the binding of some antibodies. Encouragingly, the patients’ antibodies still provided substantial protection by binding to the spike. This indicates that even though some antibodies do not bind as strongly to the new variant, vaccination will still be effective.
The second paper ‘Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera’ led by the same University of Oxford team focuses on a structure-function analysis of the South African variant (B.1.351) using a large number of serum samples from convalescent patients and vaccinated individuals. In a number of cases, it would appear that convalescent and some vaccine serum offer limited protection against this variant. In particular, a group of highly effective antibodies that feature in the immune response of many individuals are prevented from binding by a combination of two mutations: K417N and N501Y whilst E484K acts to evade other important antibodies. These mutations may help the virus by binding more tightly to the cell improving its transmission.
There is, however, good news in the third paper - ‘Antibody evasion by the Brazilian P.1 strain of SARS-CoV-2' as their research shows that the Brazilian variant of coronavirus may be less resistant to vaccines than had been feared. However, although the Brazilian variant in some ways closely resembles the South African variant it does not escape from the antibody response formed when individuals are naturally infected or vaccinated to the same degree as the South African variant does, meaning that vaccination should help to control the spread of the virus. New vaccines based on the South African variant are therefore a high priority for new vaccine development or modification.
14 April 2021 - Experiment with 2533 fragments compounds generates chemical map to future antiviral agents.
In record time, an international team carried out a massive crystallographic screening and computational docking effort, pointing the way to new SARS-CoV-2 inhibitors. Using Diamond’s XChem facility they identified new chemical matter which primarily targets the active site of the macrodomain of SARS-CoV-2/Coronavirus 2. This is important because this new chemical matter could be developed into inhibitors of a promising antiviral target which will make viruses non infectious. The international effort discovered 234 fragment compounds that directly bind to sites of interest on the surface of the protein, and map out chemical motifs and protein-compound interactions that researchers and pharmaceutical companies can draw on to design compounds that could be developed into antiviral drugs. This work is thus foundational for preparing for future pandemics.
Their research published in Science Advances provides a template for how to develop directly-acting antivirals with novel modes of action, that would combat COVID-19 by suppressing the SARS-CoV-2 viral infection. The study involved a crystallographic fragment screen of the Nsp3 Mac1 protein by an open science collaboration between researchers from the University of Oxford, the XChem platform at Diamond Light Source, the UK’s national synchrotron, and researchers from the QCRG Structural Biology Consortium at the University of California San Francisco. Their paper: Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking explains how using Crystallographic screening of diverse fragment libraries resulted in 214 unique macrodomain-binding fragments of 2533 screened. Also, an additional 60 molecules were selected from docking more than 20 million fragments, of which 20 were crystallographically confirmed.
7 April 2021 - First images from eBIC of cells exposed to COVID-19 vaccine reveal the production of native-like Coronavirus spikes.
New research has for the first time directly visualised the protein spikes that develop on the surface of cells exposed to the Oxford-AstraZeneca vaccine and compared these to the protein spike of the SARS-CoV-19 coronavirus. The images, gained using the powerful technique of CryoET at the Electron Bio-Imaging Centre (eBIC) at Diamond Light Source, show that the spikes are highly similar to those of the virus and support the modified adenovirus used in the vaccine as a leading platform to combat COVID-19.
26 March 2021 - New targets for antibodies in the fight against SARS-CoV-2.
Due to the way antibodies are made, each person that is infected with COVID-19 has the potential to produce many antibodies that target the virus in a slightly different way. By using Diamond, applying X-ray crystallography and cryo-EM, an international research team led by scientists from Diamond and Oxford were able to visualise and understand how antibodies interact with and neutralize the virus. The research article in the journal Cell is one of the most comprehensive studies of its kind so far, examining antibodies from a large cohort of COVID-19 patients. Their results show that there are many different opportunities to attack the virus using different antibodies over a much larger area than initially thought/mapped. The article is available online now and will be published in print on 15 April 2021. This has also provided a basis for understanding the effect on antibody neutralisation of mutations in several of the variant viruses which are now a cause for concern around the world.
Diamond created a highly detailed scientific animation showing how the SARS-CoV-2 (or COVID-19) virus infection mechanism works at the cellular level. The aim was to inform researchers and the public and share the knowledge that scientists working with Diamond have uncovered on how the virus replicates itself. The genome replication, assembly and egress of the virus is a multistage process that is critically important as it bears the means of medical intervention to stop infection.
This is the first time the virus has been depicted in this way, showing in detail how the virus infection mechanism operates based on our understanding so far. The animation is entirely based on the work achieved at Diamond using both Cryo-EM and X-ray Crystallography. Watch the full animation below. There is also a short two-minute animation.
November 2020 - Studying the viral infection in the native cellular context reveals that SARS-CoV-2 replication induces profound cytopathic effects in host cells.
A research group led by Peijun Zhang, Professor of Structural Biology, Division of Structural Biology, University of Oxford, and Director of eBIC, Diamond Light Source, investigated SARS-CoV-2 replication under near-native conditions, exploiting a unique correlative imaging approach to depict the entire SARS-CoV-2 infected cell. Their results revealed at the whole cell level profound cytopathic effects of SARS-CoV-2 infection and have enabled modelling of SARS-CoV-2 genome replication, virus assembly and egress pathways. Understanding the multistage infection process is critically important as it bears the means of medical intervention to help combat COVID-19.
October 2020 - Structural Biology identifies new information to accelerate structure-based drug design against Covid-19.
New research that has identified potential ways forward to rapidly design improved and more potent compounds in the fight against COVID-19. The work is the result of a massive fragment screening effort to develop an antiviral targeting the SARS-CoV-2 main protease. The project was led by Martin Walsh, Deputy Life Sciences Director at Diamond Light Source; Frank von Delft, Professor of Structural Chemical Biology at the University of Oxford and Principal Beamline Scientist of I04-1/XChem at Diamond; and Nir London, Assistant Professor at the Weizmann Institute Israel. The team combined mass spectrometry with the XChem facility at Diamond, to rapidly identify lead compounds for drug development to treat COVID-19.
August 2020 - Structural Biology reveals new target to neutralise COVID-19.
Diamond, along with an international team of researchers, discovered a new and highly conserved site on the SARS-CoV-2 virus that can be neutralised by a specific antibody. Previous studies have reported that antibodies that block the virus interaction with the human receptor (ACE2) have a significant neutralising effect and can be used to save the lives of critically ill patients. However, this study published in Nature Structural and Molecular Biology describes a different target that can be bound in synergy with ACE2 blocking antibodies for a stronger neutralising effect. Together, with a group at a hospital in Taiwan, the team using the Electron Bio Imaging Centre (eBIC) at Diamond identified antibodies from a convalescent patient that could create a real potential for a drug target.
July 2020 - Engineered llama antibodies neutralise COVID-19 virus.
A collaboration with researchers from Diamond Light Source, the Rosalind Franklin Institute, Oxford University and Public Health England discovered that antibodies derived from llamas were shown to neutralise the SARS-CoV-2 virus in lab tests.They hope the antibodies – known as nanobodies due to their small size – could eventually be developed as a treatment for patients with severe COVID-19.
May 2020 - UK consortium launches COVID-19 Protein Portal to provide essential reagents for SARS-CoV-2 research.
The Wellcome Trust and UKRI brought together leading centres of protein engineering and production including Diamond in an Open Science initiative enabling UK scientists to access protein reagents for critical research relating to SARS-CoV-2 free of charge.
April 2020 - COVID Moonshot.
Call for Chemists to contribute to the fight against COVID-19 Diamond, start-up company PostEra Inc. and an international group of scientists from academia and industry teamed up to form this ground-breaking non-profit initiative. Their unprecedented aim is to develop a clinically effective antiviral more rapidly than ever before, by crowdsourcing designs of new inhibitors from chemists around the world who are mining the rich “fragment” data measured at Diamond in record time during March and April. All data will be released in real time and in the open to enable worldwide collaboration and rapid progress.
This collaboration has created a clear design-to-clinic strategy and timeline. Researchers can submit their designs to PostEra, who are running machine learning algorithms in the background to triage suggestions and generate synthesis plans to enable a rapid turnaround. Promising compounds will then be synthesised and tested for antiviral activity and toxicity. This is ongoing and continuing drug discovery work.
March 2020 - Joint initiative announced to accelerate the search for COVID-19 drugs.
Jointly with Exscientia and Scripps Research, Diamond in this new transatlantic partnership seeks to accelerate the path to clinical trials for potential COVID-19 antiviral treatments. Using Diamond's research on COVID-19 and research facilities, Exscientia will screen nearly every known approved and investigational drug - 15,000 clinical drug molecules - against COVID-19 drug targets to search for rapid treatments.
Find out more about Diamond's response to virus research.
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