Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors | Science

Editor's Summary:  The COVID-19 pandemic prompted many groups to rethink how to perform and communicate science. Although their work has been freely available from the beginning, Boby et al. now formally report the results of the COVID Moonshot project, a fully open-science drug discovery campaign to identify, synthesize, and test inhibitors against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease, a key antiviral target (see the Perspective by Shoichet and Craik). Starting with data from a fragment-based screen, candidate inhibitor designs were crowdsourced from volunteer submitters using a variety of design approaches. An experienced team, aided by computational tools, evaluated proposals and designed synthetic routes. Noncovalent, nonpeptidomimetic inhibitors were identified and characterized functionally and structurally. Iterative medicinal chemistry and community input yielded a lead with promising bioavailability, safety, and antiviral activity. —Michael A. Funk