COVID Moonshot’s groundbreaking research introduces new nonpeptidic inhibitors for SARS-CoV-2, showcasing global collaboration and open science in advancing coronavirus therapeutics.

Although the group’s work has been freely available since its inception in March 2020, the COVID Moonshot Consortium is finally formally reporting its 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.”

Global Collaboration and Drug Discovery Efforts

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.

Innovative Drug Design and Open Science Impact

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.

Reference: “Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors” by Melissa L. Boby, Daren Fearon, Matteo Ferla, Mihajlo Filep, Lizbé Koekemoer, Matthew C. Robinson, The COVID Moonshot Consortium‡, John D. Chodera, Alpha A. Lee, Nir London, Annette von Delft, Frank von Delft, Hagit Achdout, Anthony Aimon, Dominic S. Alonzi, Robert Arbon, Jasmin C. Aschenbrenner, Blake H. Balcomb, Elad Bar-David, Haim Barr, Amir Ben-Shmuel, James Bennett, Vitaliy A. Bilenko, Bruce Borden, Pascale Boulet, Gregory R. Bowman, Lennart Brewitz, Juliane Brun, Sarma BVNBS, Mark Calmiano, Anna Carbery, Daniel W. Carney, Emma Cattermole, Edcon Chang, Eugene Chernyshenko, Austin Clyde, Joseph E. Coffland, Galit Cohen, Jason C. Cole, Alessandro Contini, Lisa Cox, Tristan Ian Croll, Milan Cvitkovic, Steven De Jonghe, Alex Dias, Kim Donckers, David L. Dotson, Alice Douangamath, Shirly Duberstein, Tim Dudgeon, Louise E. Dunnett, Peter Eastman, Noam Erez, Charles J. Eyermann, Michael Fairhead, Gwen Fate, Oleg Fedorov, Rafaela S. Fernandes, Lori Ferrins, Richard Foster, Holly Foster, Laurent Fraisse, Ronen Gabizon, Adolfo García-Sastre, Victor O. Gawriljuk, Paul Gehrtz, Carina Gileadi, Charline Giroud, William G. Glass, Robert C. Glen, Itai Glinert, Andre S. Godoy, Marian Gorichko, Tyler Gorrie-Stone, Ed J. Griffen, Amna Haneef, Storm Hassell Hart, Jag Heer, Michael Henry, Michelle Hill, Sam Horrell, Qiu Yu Judy Huang, Victor D. Huliak, Matthew F. D. Hurley, Tomer Israely, Andrew Jajack, Jitske Jansen, Eric Jnoff, Dirk Jochmans, Tobias John, Benjamin Kaminow, Lulu Kang, Anastassia L. Kantsadi, Peter W. Kenny, J. L. Kiappes, Serhii O. Kinakh, Boris Kovar, Tobias Krojer, Van Ngoc Thuy La, Sophie Laghnimi-Hahn, Bruce A. Lefker, Haim Levy, Ryan M. Lithgo, Ivan G. Logvinenko, Petra Lukacik, Hannah Bruce Macdonald, Elizabeth M. MacLean, Laetitia L. Makower, Tika R. Malla, Peter G. Marples, Tatiana Matviiuk, Willam McCorkindale, Briana L. McGovern, Sharon Melamed, Kostiantyn P. Melnykov, Oleg Michurin, Pascal Miesen, Halina Mikolajek, Bruce F. Milne, David Minh, Aaron Morris, Garrett M. Morris, Melody Jane Morwitzer, Demetri Moustakas, Charles E. Mowbray, Aline M. Nakamura, Jose Brandao Neto, Johan Neyts, Luong Nguyen, Gabriela D. Noske, Vladas Oleinikovas, Glaucius Oliva, Gijs J. Overheul, C. David Owen, Ruby Pai, Jin Pan, Nir Paran, Alexander Matthew Payne, Benjamin Perry, Maneesh Pingle, Jakir Pinjari, Boaz Politi, Ailsa Powell, Vladimír Pšenák, Iván Pulido, Reut Puni, Victor L. Rangel, Rambabu N. Reddi, Paul Rees, St Patrick Reid, Lauren Reid, Efrat Resnick, Emily Grace Ripka, Ralph P. Robinson, Jaime Rodriguez-Guerra, Romel Rosales, Dominic A. Rufa, Kadi Saar, Kumar Singh Saikatendu, Eidarus Salah, David Schaller, Jenke Scheen, Celia A. Schiffer, Christopher J. Schofield, Mikhail Shafeev, Aarif Shaikh, Ala M. Shaqra, Jiye Shi, Khriesto Shurrush, Sukrit Singh, Assa Sittner, Peter Sjö, Rachael Skyner, Adam Smalley, Bart Smeets, Mihaela D. Smilova, Leonardo J. Solmesky, John Spencer, Claire Strain-Damerell, Vishwanath Swamy, Hadas Tamir, Jenny C. Taylor, Rachael E. Tennant, Warren Thompson, Andrew Thompson, Susana Tomásio, Charles W. E. Tomlinson, Igor S. Tsurupa, Anthony Tumber, Ioannis Vakonakis, Ronald P. van Rij, Laura Vangeel, Finny S. Varghese, Mariana Vaschetto, Einat B. Vitner, Vincent Voelz, Andrea Volkamer, Martin A. Walsh, Walter Ward, Charlie Weatherall, Shay Weiss, Kris M. White, Conor Francis Wild, Karolina D. Witt, Matthew Wittmann, Nathan Wright, Yfat Yahalom-Ronen, Nese Kurt Yilmaz, Daniel Zaidmann, Ivy Zhang, Hadeer Zidane, Nicole Zitzmann and Sarah N. Zvornicanin, 10 November 2023, Science.
DOI: 10.1126/science.abo7201