Research Focus
Global Collaborators ‘cunning plan’ for affordable, accessible oral anti-virals
Earlier this year a consortium led by international scientists from the global, non-profi t, open-science COVID Moonshot was awarded an initial $68 million from the US National Institutes of Health (NIH). The ultimate objective of the project is to discover and develop globally accessible and affordable novel oral antivirals to combat COVID-19 and future pandemics: specifi cally to produce preclinical candidates against six viral targets.
The consortium’s strategy is to create an AI-driven Structure-enabled Antiviral Platform (ASAP), using cutting-edge technology such as advanced structural biology, fragment screening, AI and machine learning, as well as computational chemistry on Folding@home, the world’s largest distributed computing platform to build a robust and open access antiviral discovery pipeline.
The ASAP consortium is truly global with active contributors from the West and East coasts of the USA including New York, Standford, Palo Alto, Seattle, Geneva - Switzerland, Tel Aviv – Israel, Oxford -UK and Brazil. It is one of the nine worldwide Antiviral Drug Discovery (AViDD) Centres for Pathogens of Pandemic Concern funded by the National Institute of Allergy and Infectious Diseases (NIAID) as part of the Antiviral Program for Pandemics (APP).
All AViDD Centres will conduct
research on the identification and validation of novel viral targets, with an eye to identify small molecules and biotherapeutics that directly inhibit viral targets. As drug candidates are identified and evaluated for properties such as potency and breadth, the most promising will enter late-stage preclinical development.
ASAP was built on the success of the COVID Moonshot, that began in March 2020. It rapidly identified potent antivirals targeting the main protease of the SARS-CoV-2 virus which are currently undergoing a preclinical program funded by the Wellcome Trust / COVID-19 Therapeutics Accelerator. The open science data publicly shared by Moonshot additionally enabled the identification of another promising COVID-19 therapeutics developed by the Japanese pharmaceutical company Shionogi. “The rapid progress of Moonshot demonstrated the power of AI-driven drug design,” said Dr Alpha Lee, Chief Scientific Officer of PostEra and a founder of the COVID Moonshot. “Our algorithms generate molecules with optimised properties that can quickly be made and tested in the lab and help us select the most important experiments. ASAP will take this to the next level.” Dr Lee is one of the leaders of ASAP.
Two of the UK collaborators driving the ASAP centre talked to Labmate about their roles – Lizbé Koekemoer, Team Leader at the Centre for Medicines Discovery (CMD) at the University of Oxford and Daren Fearon, Senior Beamline Scientist at Diamond Light Source, the UK’s national synchrotron.
Lizbé explained that the ASAP project follows shortly after formation of the Oxford university’s Centre for Medicines Discovery (CMD) which, amongst others, incorporates the old Structural Genomic Consortium (SGC) Oxford and several small research facilities (SRFs).
“The SGC had a lot experience in creating what we call Target enabling packages (TEPs) – a knowledge package
to target proteins that allows for their rapid biochemical and chemical exploration and characterisation. Our experience in developing TEPs is a natural fit to a programme such as ASAP.”
In these early stages of the project the team is taking the time to learn about the different viruses, how they work and getting to know their antiviral properties. This knowledge is used to formulate hypotheses on how to target these viruses rather than just taking shots in the dark. Lizbé and the Oxford teams use these insights to identify which proteins to produce for further studies.
This really is science in action, making a difference to real life problems
“This is applied science not just theory. And it’s exciting because we have access to a lot of high-level technology like the synchrotron at Diamond. This really is science in action, and we will make a difference to real life problems,” Lizbé commented.
The CMD has four small research facilities (SRF) which drive different parts of projects including protein production, assay development, crystallisation and capturing all the data in our central database SCARAB and electronic notebooks (ELN). “For ASAP we have a list of protein targets to work on. I coordinate the crystallography SRF and my team optimises the crystallisation conditions for the various projects being undertaken in the ASAP centre and pass them onto Diamond to do a fragment screen on the XChem beamline.”
“But I need to make clear that it’s just not my team doing the work. Dr Eleanor Williams who coordinates the protein production SRF, is the actual starting point for our work. Her team takes the initial target list and designs and clones expression constructs with different boundaries and tags. We produce proteins from these different constructs to see which expresses soluble protein. The best ones (or the ones that work), we use, to produce large quantities of protein that will be used in either crystallisation trials or assays (done by Dr Oleg Fedorov in the Biochemical and Biophysical SRF). For crystallisation we will try any literature conditions that exist, and in parallel set up crystal trays with as many coarse screens (screening for conditions for crystallisation covering a wide range of pHs and reagents) as possible. All crystals obtained are sent to the beamline and we will optimise the crystallisation conditions around the most promising ones.” adds Lizbé. “All the time in the background the Research Informatics SRF, run by Professor Brian Marsden and Dr Tamas Szommer, is actively keeping track of our data.”
Lizbé Koekemoer, Centre for Medicine Discovery, University of Oxford
Daren Fearon in XChem Lab - Copyright Diamond Light Source Ltd 2022
XChem Beamline I04-1 - Copyright of Diamond Light Source Ltd 2022
INTERNATIONAL LABMATE - NOVEMBER 2022
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