Herein we provide a living summary of the data generated during the COVID Moonshot project focused on the development of SARS-CoV-2 main protease (Mpro) inhibitors. Our approach uniquely combines crowdsourced medicinal chemistry insights with high throughput crystallography, exascale computational chemistry infrastructure for simulations, and machine learning in triaging designs and predicting synthetic routes. This manuscript describes our methodologies leading to both covalent and non-covalent inhibitors displaying protease IC50 values under 150 nM and viral inhibition under 5 uM in multiple different viral replication assays. Furthermore, we provide over 200 crystal structures of fragment-like and lead-like molecules in complex with the main protease. Over 1000 synthesized and ordered compounds are also reported with the corresponding activity in Mpro enzymatic assays using two different experimental setups. The data referenced in this document will be continually updated to reflect the current experimental progress of the COVID Moonshot project, and serves as a citable reference for ensuing publications. All of the generated data is open to other researchers who may find it of use.

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Nearly 15 months ago, a large, fast-moving and unscheduled experiment began: probing a key protein of the coronavirus SARS-CoV-2 to find chemical starting points for drug discovery. The end point was to develop pills that people could take to treat COVID-19 and related diseases.This experiment pulled together a spontaneous, open, global, Twitter-fuelled collaboration called the COVID Moonshot. Urgency and a commitment to working openly recruited more than 150 active participants, spanning a huge range of expertise and technology across academia, biotechnology, pharmaceuticals and more, all working without claiming intellectual property. Open drug-discovery efforts are invariably super slow -ours has been an express train on tracks we have laid down as we go. It is a way of working that none of us realized was possible.The intention for the original experiment was simply to help jump-start large drug-discovery initiatives that could draw directly on our data. In those first weeks, before the pandemic had taken hold in the United Kingdom or Israel (where the experiment started), we expected that some international effort was already in the works for countries and companies to collaborate on finding COVID-19 treatments, as was happening with vaccines.Disappointingly, from the start of the COVID-19 fight, international funders decided to support only the development of repurposed small-molecule drugs and monoclonal antibodies to deliver treatments quickly, neglecting other approaches. The world seemed to give up on new antivirals before they even started, agreeing on a self-fulfilling prophesy that such drugs would take years to develop. Few seemed willing to contemplate such a timescale for this pandemic. Our first grant proposal was rejected, so we had to find a different way to press on.

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The primary target of a novel series of immunosuppressive 7-piperazin-1-ylthiazolo[5,4- d]pyrimidin-5-amines was identified as the lipid kinase, PI4KIIIβ. Evaluation of the series highlighted their poor solubility and unwanted off-target activities. A medicinal chemistry strategy was put in place to optimize physicochemical properties within the series, while maintaining potency and improving selectivity over other lipid kinases. Compound 22 was initially identified and profiled in vivo, before further modifications led to the discovery of 44 (UCB9608), a vastly more soluble, selective compound with improved metabolic stability and excellent pharmacokinetic profile. A co-crystal structure of 44 with PI4KIIIβ was solved, confirming the binding mode of this class of inhibitor. The much-improved in vivo profile of 44 positions it as an ideal tool compound to further establish the link between PI4KIIIβ inhibition and prolonged allogeneic organ engraftment, and suppression of immune responses in vivo.