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'Faced with global vaccine inequality and the rapid spread of variants of concern, the need for easily-accessible antiviral therapeutics to treat people with COVID-19 is as pressing as ever, especially in low- and middle-income countries,' said Annette von Delft, Translational Scientist at the University of Oxford and NIHR Oxford Biomedical Research Centre (BRC).
'Most of the research and funding efforts early in the pandemic focused predominantly on repurposing of existing small molecule drugs and the more rapid development of novel monoclonal antibodies. Now, with the realization that COVID-19 will be a global issue for the foreseeable future we urgently need to develop novel antiviral therapeutics. We are therefore thrilled to receive this critical funding from Wellcome and hope it can lead to more support,' said Alpha Lee, Chief Scientific Officer at PostEra and Faculty Member at the University of Cambridge.
The Moonshot started as a spontaneous virtual collaboration in March 2020. As countries locked down, a group of scientists, academics, pharmaceutical research teams and students began a worldwide, twitter-fuelled race against the clock to identify new molecules that could block SARS-CoV-2 infection and develop pills that would be readily available to the most vulnerable communities.
The University of Oxford, the NIHR Oxford BRC and Diamond Light Source, the UK's national synchrotron science facility, have been key players in progressing the non-profit, open-science idea and early drug discovery effort of the COVID Moonshot initiative. Close collaboration between them and other contributors around the world enabled the rapid development of promising lead compounds.
The appointment of translational scientists working on pre-clinical small molecule drug development by the Oxford BRC prior to the COVID pandemic has been crucial for the success of the project. Annette von Delft has been leading the pre-clinical cellular assays and translational efforts of the Moonshot consortium over the last year. She has been instrumental in securing the £8m Wellcome Trust award in close partnership with the Drugs for Neglected Diseases initiative (DNDi) and will be deputy lead on the pre-clinical development of the oral SARS-CoV-2 MPro inhibitor. MPro is key protease enzyme of a coronavirus that speeds up the breakdown of proteins.
Ultimately more than 150 scientists - including dozens of students who put their own projects on hold – joined Moonshot to crowdsource ideas for molecular compounds, model them and evaluate them in-vitro against the virus. Their goal: a safe, globally affordable, not-for-profit oral treatment for COVID-19 and related viral pandemics.
'Open drug discovery efforts are invariably super slow – ours has been an express train on tracks we have laid down as we go,' wrote Frank von Delft, Professor of Structural Chemical Biology at the University of Oxford and Principal Beamline Scientist at Diamond Light Source, in a comment published in June in Nature. 'It is a way of working none of us realised was possible.'
Collaborators of the Moonshot project include academic and industrial groups such as Diamond Light Source; the Weizmann Institute of Science (Israel); the Nuffield Department of Medicine at the University of Oxford (UK); PostEra (US/UK); the Memorial Sloan Kettering Cancer Center (US); various drug discovery consultants including MedChemica Ltd (UK), Thames Pharma Partners (US), and Compass Business Partners (UK); and the Switzerland-based DNDi, which is taking the lead in coordinating the Wellcome-funded drive towards the clinic.
Thanks to this unprecedented collaboration, rapid progress has been made and the team now aims to identify pre-clinical candidate molecules by the end of 2021 – compounds that will be simple to manufacture in the form of pills and which will exert an anti-viral effect via potent inhibition of the main protease (MPro) of the SARS-CoV-2 virus.
The funding from Wellcome is vital as the project enters a phase there the molecules are amended, optimised and tested to develop them into a safe treatment. From its inception, this project has focused on the needs of low- and middle-income countries and the most vulnerable communities, by striving to identify drugs that remove the need of cold chain or injection, and by ensuring that the results are equitably accessible,' said Ben Perry, Discovery Open Innovation Leader at DNDi. 'The project is based firmly in an open science environment and prioritized simplicity of synthesis of the future drugs, in order to facilitate manufacturing by any interested producer.'
Nir London, Senior Scientist at the Weizmann Institute of Science, added: 'If drug discovery efforts that were launched during the 2003 SARS epidemic had persevered and had been funded to completion, relevant anti-coronavirus drugs would have been more readily available when COVID-19 hit.
'Now is the time to plan for the future. In addition to addressing this current pandemic, which is not showing signs of slowing, we want to develop one or more novel pan-coronavirus antiviral molecule for future outbreaks. We also want to provide an open platform to accelerate the response time when new pandemics arise.'
All the generated discovery scientific data and the general learnings of the project will be put in the public domain. Moonshot data is already available online to enable others to freely build on its work; the project has already generated over 50% of known structural information on the main protease, a key protein in SARS-CoV-2. The first clinical trials are expected in 2022.