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Just 10 months ago most of us had never heard of COVID-19 – now it is a term we refer to several times a day as we learn to live and work alongside this pandemic. Six months ago, when we entered our first lockdowns, little was known about this particular virus, how it worked to infect us and how it spreads. However, in just over six months scientists all over the globe, often working in collaboration with the UK’s Synchrotron, Diamond Light Source, have made huge progress in understanding how COVID-19 operates and as a result, they have opened the doors to real possibilities of solutions and therapies.
Timed to coincide with World Science Day (10th November) 2020, a new video animation has been released showing how the SARS-CoV-2 (or COVID-19) virus infection mechanism works at the cellular level. The intention is to inform and share with the public the knowledge that scientists working with Diamond have uncovered 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 two-minute, shorter animation.
Professor David Stuart, Life Sciences Director at Diamond and Joint head of Structural Biology at the University of Oxford, said:
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 further closer to our goal of finding therapies. Our hope is that this animation will help articulate achievements so far.
The animation was created by combining a set of images achieved via various scientific imaging techniques from synchrotron-based crystallography and imaging to high resolution Cryo-electron microscopy to depict the entire SARS-CoV-2 infected cell. This unique approach gives a holistic view of SARS-CoV-2 infection, from the whole cell to individual molecules, revealing unseen pathways of the virus assembly and egress, and the cellular structural changes caused by the virus. Further development in the area of labelling individual viral and relevant host proteins involved in the process will be essential to allow a correlative structural analysis at the molecular level.
Prof. Stuart added that in response to the outbreak of COVID-19 efforts from scientists around the world have yielded a great deal of knowledge on the etiological agent.
Structural understanding of the viral components is key to the discovery of therapeutics and so far work has concentrated on virial spikes, main protease, RNA polymerase and other non-structure proteins, as well as spike interactions with host receptor ACE2 and neutralising antibodies, using a range of tools from synchrotron based X-ray crystallography to cryoEM and cryoET.
These latter two techniques are essential for in vitro and in situ study in the context a virion. However, all these techniques will be important in tackling the challenges that lie ahead with the remaining viral components, which are small, flexible and heterogeneous, and some are even membrane bound, but they are pivotal in understanding the entire virus architecture and its genome organisation.
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. It is also 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.
November: 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: 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: 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: 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: 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: 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.
March: 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.
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