5
The criteria the CMD teams are trying to meet for the crystals are: Reproducible crystallisation conditions o SBS-format 3-lens midi SwissCi plates with drop volumes of 100-600 nl o Well defi ned cryo-protecting procedure o PEG-based crystallisation buffer and room temperature crystallisation preferred
• Crystal size and robustness o Can tolerate manipulation when harvesting and high solvent concentrations
• Consistent X-ray diffraction o Ideally < 2.5 Å resolution
• Suitable crystal packing o Demonstrated ability to soak compounds into site of interest
Once they have the crystallisation protocols fi gured out, they will transfer the protocol and protein to the Diamond team who will set up the crystal trays for XChem screening.
We are doing drug discovery in a very different
way - open and not secretive. ASAP will target viral families and will also target those that have been historically neglected by the market. The initial focus will be on coronaviruses (responsible for the current COVID-19 pandemic as well as earlier SARS and MERS epidemics) and will aim to address fl aviviruses (responsible for large endemic diseases such as Dengue and Zika whose vectors will inevitably come to the United States due to climate change) and picornaviruses (responsible for devastating diseases such as polio).
Researcher Dr Ellie Williams, from the Centre for Medicine Discovery, University of Oxford, looks at a culture used to produce the proteins used for study - Copyright Brain Tumour Charity
If we can get this right for antivirals, we could get it right for antibacterials
Although ASAP is doing drug discovery for anti-virals, the technology and science they are progressing can be applied to anything. “CMD are very much part of the goal to solidify this discovery pipeline. If we can get this right for antivirals, we could get it right for antibacterials; or indeed any other type of drug discovery process that’s needed.” Lizbé added.
What’s different about this whole process is that all the ASAP fragment screening results will be made publicly available immediately to help stimulate other drug discovery efforts. The goal is to accelerate the process from fragment to preclinical candidate, using AI and other computational methods.
This projects’ initial focus has been on getting all the necessary people, technology and processes in place to enable the teams to undertake the massive amount of work they expect over next few years. However, they have been able to make a rapid start by using several warm prospects from Diamond’s XChem programme. They have already screened 9 different SARS-CoV-2 targets and are already starting to collect more data to release into the public domain. They expect to make more fragment screens on new targets available by year end.
“I believe that one of the true successes of the Moonshot initiative was that other people started using our data to produce clinical candidates and sharing results in an area that is historically very secretive. We are all taking an open science approach to everything we produce. For ASAP, results will be made available as close to real time as possible for the hit-to-lead process. It feels a bit crazy but people around the world really want to share their knowledge and come together to solve some of these problems, they willingly give up time and resources to investigate compounds.” concluded Daren.
Daren Fearon in XChem Beamline with ASAP Puck - Copyright of Diamond Light Source Ltd 2022
Daren Fearon’s role in ASAP is as a co- investigator in charge of the structural biology core. It’s his responsibility to make sure they can deliver fragment screening results as quickly as possible and fulfi l the potential of having a high-throughput beamline integrated entirely into an open science, drug discovery project. “We are doing drug discovery in a very different way. We are trying to be completely open and not secretive. The Moonshot showed that the traditional drug discovery pipeline doesn’t work for a pandemic. Working openly allows us to enable science on all targets that we think are relevant, no matter any potential future profi t. Especially the more neglected targets that have been ignored by the western world - where drug discovery hasn’t been done thoroughly because traditional big pharma can’t recoup the costs of doing the research.”
As Daren and Lizbé were very active on the Moonshot they were keen to get involved in the ASAP project and share their experience working on data gathering, the structural biology, and of working at speed on hundreds of crystals. “A lot of time at our fi rst ASAP meetings was spent discussing the learnings from Moonshot as our collaborators had never seen a project with so many protein structures,” stated Daren explaining that Moonshot’s big advantage was its access to the Diamond Synchrotron and the XChem beamline for fragment-based screening which is now a well-established powerful approach to early drug discovery. Access to XChem for ASAP projects is fully costed as part of the grant so the collaborators can get onto the beamline when needed. This is very rare as it can be quite a bottleneck in industry.
“Few drug companies have this kind of access to our beamline, so as with Moonshot, we hope to be able to push the numbers a lot higher than has ever been done before with similar projects. Our previous work enabled the development of new software and methods as well as speeding up access to results - never before shared publicly in these kinds of numbers,” explained Daren. “Moonshot was a very organic collaboration with people just volunteering and we quickly found that if people want to work together and don’t care who gets the credit it’s amazing what you can do – especially when you’re not all bound by secrecy, IP or legal limitations.”
The focus for ASAP is to harness the technique to proceed rapidly to potent compounds. Diamond’s part is to carry out mainly fragment screenings but also to provide structural biology support for hit-to-lead development on 10 different protein targets across a variety of different viruses and optimise preclinical candidates.
A view of the CMD labs - Copyright Chiara MacCall
The key goals of ASAP is to prepare globally accessible, low-cost therapeutics with the potential for rapid progression into clinical trials, to ensure equitable access to all should any future pandemic arise. ASAP partners include the Diamond Light Source (UK); PostEra (USA); the Memorial Sloan Kettering Cancer Centre (USA); the Weizmann Institute of Science (Israel); Medchemica (UK); Mount Sinai (USA); Stanford University School of Medicine (USA); the Fred Hutchinson Cancer Center (USA), and the Drugs for Neglected Diseases initiative (global), as well as a vast global network of scientists and industry collaborators.
More details on ASAP and its mission can be found at
http://asapdiscovery.org Centre for Medicines Discovery – CMD see:
https://www.cmd.ox.ac.uk/platforms.
The Diamond Light Source – XChem :
https://www.diamond.ac.uk/Instruments/Mx/ Fragment-Screening.html
WWW.LABMATE-ONLINE.COM
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