Although the group’s work has been freely available since its inception in March 2020, the COVID Moonshot Consortium is finally formally reporting their results. The COVID Moonshot – an open-science, crowdsourced, and patent-free drug discovery campaign targeting the SARS-CoV-2 virus – has yielded a wealth of data on the virus’s main protease, including insights that could pave the way for the development of new and better therapeutics. “The lead therapeutics described by [these researchers] may not be ready in time to affect the current pandemic, considering the timelines and challenges of drug approval,” write Brian Shoichet and Charles Craik in a related Perspective. “Nevertheless, the compounds and the techniques used to identify them may well affect human health in the future.”
The novel collaboration included more than 200 volunteer scientists from 47 academic and industrial organizations spanning 25 countries. “The COVID Moonshot provides an example of open science drug discovery leading to advances in infectious diseases drug discovery – a research area of grave public importance, but one that is chronically underfunded by the private sector,” write Melissa and colleagues. Due to its essential role in viral replication, the SARS-CoVB-2 main protease (Mpro) is an attractive target for antiviral development. Current SARS-CoV-2 Mpro inhibitor drugs, such as those drawn from preexisting antiviral pipelines like Paxlovid and Xocova, have shown clinical success. However, the use of these compounds has remained relatively limited and their peptidomimetic and covalent scaffolds create issues for synthesis and administration. Here, Boby et al. describe the discovery of a novel, noncovalent, and nonpeptidic inhibitor scaffold that is chemically distinct from current Mpro inhibitors. Leveraging a crowdsourcing approach and the combined expertise of hundreds of individuals worldwide, Boby et al. describe their open-science drug discovery campaign, which included machine learning, molecular simulations, and high-throughput structural biology and chemistry to assemble a detailed structural map of the SARS-CoV-2 main protease and its biochemical activity. Of the more than 18,000 compound designs produced by the COVID Moonshot Consortium, the authors identified several noncovalent, nonpeptidomimetic inhibitors, including a lead compound with promising bioavailability, safety, and antiviral activity. All compound designs from the project have been shared openly, creating a rich, open, and intellectual property–free knowledge base for future anticoronavirus drug discovery.
Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors
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