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New COVID Moonshot paper shows Open Science is a viable route to early drug discovery, describing first-ever crowd-sourced small molecule discovery and announcing a potent SARS-CoV-2 antiviral lead compound
The work of the COVID Moonshot Consortium has now been published in the prestigious journal Science, revealing their discovery of a potent SARS-CoV-2 antiviral lead compound. It also reflects on the success of its open science approach in launching a patent-free antiviral discovery program to rapidly develop a differentiated lead in response to a pandemic emergency.
Work on Alzheimer’s and Parkinsons by multidisciplinary team from Keele and Warwick Universities into how fundamental chemical processes occur in the brain may lead to new innovative strategies to improve brain health with ageing.
Today Diamond is celebrating UNESCO’s World Science Day - which takes place every 10 November - to raise awareness of the significant role of science in society, by highlighting some of the groundbreaking science that it is helping its users to achieve. Many of the discoveries enabled by Diamond have been crucial to some of the most defining science in recent history – from kickstarting Covid treatments and deconvoluting the efficacy of the Covid vaccine, to advancing treatment for many diseases from HIV, Foot and Mouth Disease to Cancer, and even identifying a plastic-eating enzyme that may help solve the plastic pollution of our planet.
Gianluigi Botton, CEO of Diamond Light Source comments,
Every day here at Diamond, we are proud to be working with leading scientists and academics like the COVID Moonshot Consortium and the Keele and Warwick University collaboration who come from all over the world to conduct innovative and inspired research using our facility. Bringing together experts in physical and life science innovations, cross disciplinary teams, and access to collaborative facilities allows our users to shine their brilliance on new technologies, treatments, sustainable materials and climate solutions for the many 21st century challenges we face.
The COVID Moonshot initiative started as a spontaneous virtual collaboration in March 2020, when a group of scientists and students from academia and biopharma, triggered by a Twitter appeal, joined forces in a race against the clock to identify new molecules that could block the SARS-CoV-2 virus. This unprecedented crowdsourced and fully open collaboration of more than 200 scientists, rapidly identified and developed novel compounds with excellent antiviral activity against a key enzyme of the SARS-COV-2 virus, namely the main protease (Mpro). The lead candidate is now in pre-clinical evaluation in collaboration with Drugs for Neglected Disease initiative (DNDi). The COVID Moonshot is dedicated to the discovery of safe, globally affordable antiviral drugs against COVID-19 and future viral pandemics, and is pioneering a straight-to-generic, patent-free approach.
The consortium’s paper reports on the discovery of a non-covalent, non-peptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Their approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. It built on data from a large experiment, performed in record time at the start of the pandemic, at Diamond’s XChem facility for crystallographic fragment screening using Diamond’s high-throughput crystallography. In the experiment, 1,495 fragment-soaked crystals were screened within weeks to identify 78 hits that densely populated the enzyme’s active site.
The team were able to generate a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>840 ligand-bound X-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2,400 compounds) for this campaign were shared rapidly and openly, creating a rich open and IP-free knowledge base for future anti-coronavirus drug discovery.
By making all data immediately available, with all compounds purchasable from the Ukrainian chemistry supplier Enamine, the consortium aims to accelerate research globally along parallel tracks following up on their initial work. “The data set enclosed in the Science publication provides a unique resource linking comprehensive structural data, fragment hits, multiple chemical scaffolds, as well as biochemical and cellular assay data that can be viewed and exploited by other scientists”, states Dr Lizbe Koekemoer, one of the lead authors and a team leader at the Centre for Medicines Discovery, University of Oxford.
Dr Daren Fearon, another lead author and Senior Beamline Scientist at Diamond Light Source, who leads the XChem facility, adds;
This is the first time such a large number of protein-ligand structures have been generated for a drug discovery campaign and released in the public domain. It is a testament to Diamond’s high-throughput crystallography infrastructure, but also the astonishing coordination across many research groups worldwide under enormous pressure.
As a striking example for the impact of open science, the Shionogi clinical candidate S-217622, which is available in Japan under emergency approval as Xocova [ensitrelvir], was identified using the data generated at Diamond and openly released.
Senior author Prof Frank von Delft, Principal Beamline Scientist at Diamond, Professor for Structural Chemical Biology at University of Oxford, and one of the founders of the consortium, comments,
Open science efforts have transformed many areas of biosciences. The COVID Moonshot provides an exemplar of a viable route to open science early drug discovery leading to advances in infectious diseases drug discovery—a research area of grave public importance but one which is chronically underfunded by the private sector. The Moonshot structure-enabled drug discovery campaign targeting the coronavirus main protease is providing a roadmap for the potential development of future antivirals.
This collaborative research, probing the chemical changes that occur in diseased brain tissue is led by Prof Joanna Collingwood (University of Warwick) and Prof Neil Telling (Keele University), joined by Race Against Dementia Fellow, Dr Jake Brooks (Warwick) and Lecturer in Nanoscale Bioscience, Dr James Everett (Keele). Studying how fundamental chemical processes occur in the brain is crucial for understanding neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Ultimately the research could impact our understanding of brain disease pathways, which may lead to new innovative strategies to improve brain health with ageing.
Profs Telling and Collingwood emphasise the importance of the highly sensitive and diverse measurement techniques at Diamond which allow the team to examine post-mortem brain samples at a level of intricacy inaccessible in a standard laboratory, and crucially without changing chemical properties or destroying the tissue. Prof Collingwood says;
These synchrotron approaches are making a really unique contribution to our research and the techniques and protocols we are creating, working with beamline staff at Diamond, are translatable to many other areas of biomedical research
Their work focuses on links between the excessive occurrence of abnormal clumps of aggregated proteins, and microscopic particles (known as nanoparticles) of metals such as copper and iron, that are frequently found in the brain tissue. The origin of these particles is not fully understood, but one area of investigation is the possible uptake and translocation of these miniscule metallic particles from air pollution to the brain, via the human olfactory system.
Dr James Everett is the lead author of a recent paper describing how the x-ray microscopy and spectroscopy approaches available at Diamond can be used to probe the chemical composition of the human brain at spatial scales smaller than an individual brain cell. The paper describes how these techniques are not only applicable to neurodegenerative diseases but can be used in many other fields (e.g., cancer research). Eventually, information provided by these techniques could inform diagnostic techniques and potentially treatments.
Dr Jake Brooks is using Diamond technology to examine the chemical profile of microscopic metal deposits in brain regions affected by Parkinson’s disease. The spatial scale of these deposits is minute and requires highly sensitive X-ray techniques to accurately define their chemical state. This work could not be done by any other means.
Diamond Light Source is the UK's national synchrotron science facility, located at the Harwell Science and Innovation Campus in Oxfordshire.
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