A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.

The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.

Nature. 2020 Apr 30 [Epub ahead of print]

David E Gordon, Gwendolyn M Jang, Mehdi Bouhaddou, Jiewei Xu, Kirsten Obernier, Kris M White, Matthew J O'Meara, Veronica V Rezelj, Jeffrey Z Guo, Danielle L Swaney, Tia A Tummino, Ruth Huettenhain, Robyn M Kaake, Alicia L Richards, Beril Tutuncuoglu, Helene Foussard, Jyoti Batra, Kelsey Haas, Maya Modak, Minkyu Kim, Paige Haas, Benjamin J Polacco, Hannes Braberg, Jacqueline M Fabius, Manon Eckhardt, Margaret Soucheray, Melanie J Bennett, Merve Cakir, Michael J McGregor, Qiongyu Li, Bjoern Meyer, Ferdinand Roesch, Thomas Vallet, Alice Mac Kain, Lisa Miorin, Elena Moreno, Zun Zar Chi Naing, Yuan Zhou, Shiming Peng, Ying Shi, Ziyang Zhang, Wenqi Shen, Ilsa T Kirby, James E Melnyk, John S Chorba, Kevin Lou, Shizhong A Dai, Inigo Barrio-Hernandez, Danish Memon, Claudia Hernandez-Armenta, Jiankun Lyu, Christopher J P Mathy, Tina Perica, Kala B Pilla, Sai J Ganesan, Daniel J Saltzberg, Ramachandran Rakesh, Xi Liu, Sara B Rosenthal, Lorenzo Calviello, Srivats Venkataramanan, Jose Liboy-Lugo, Yizhu Lin, Xi-Ping Huang, YongFeng Liu, Stephanie A Wankowicz, Markus Bohn, Maliheh Safari, Fatima S Ugur, Cassandra Koh, Nastaran Sadat Savar, Quang Dinh Tran, Djoshkun Shengjuler, Sabrina J Fletcher, Michael C O'Neal, Yiming Cai, Jason C J Chang, David J Broadhurst, Saker Klippsten, Phillip P Sharp, Nicole A Wenzell, Duygu Kuzuoglu, Hao-Yuan Wang, Raphael Trenker, Janet M Young, Devin A Cavero, Joseph Hiatt, Theodore L Roth, Ujjwal Rathore, Advait Subramanian, Julia Noack, Mathieu Hubert, Robert M Stroud, Alan D Frankel, Oren S Rosenberg, Kliment A Verba, David A Agard, Melanie Ott, Michael Emerman, Natalia Jura, Mark von Zastrow, Eric Verdin, Alan Ashworth, Olivier Schwartz, Christophe d'Enfert, Shaeri Mukherjee, Matt Jacobson, Harmit S Malik, Danica G Fujimori, Trey Ideker, Charles S Craik, Stephen N Floor, James S Fraser, John D Gross, Andrej Sali, Bryan L Roth, Davide Ruggero, Jack Taunton, Tanja Kortemme, Pedro Beltrao, Marco Vignuzzi, Adolfo GarcĂ­a-Sastre, Kevan M Shokat, Brian K Shoichet, Nevan J Krogan

QBI COVID-19 Research Group (QCRG), San Francisco, CA, 94158, USA., Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA., Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA., Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur, 75724, Paris, cedex 15, France., European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK., Center for Computational Biology and Bioinformatics, Department of Medicine, University of California San Diego, San Diego, CA, 92093, USA., Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, 27599-7365, USA., Zoic Labs, Culver City, CA, 90232, USA., Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, 94158, USA., Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA., J. David Gladstone Institutes, San Francisco, CA, 94158, USA., Virus and Immunity Unit, Institut Pasteur, 75724, Paris, cedex 15, France., Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, 98103, USA., Direction Scientifique, Institut Pasteur, 75724, Paris, cedex 15, France., Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur, 75724, Paris, cedex 15, France. ., Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. ., QBI COVID-19 Research Group (QCRG), San Francisco, CA, 94158, USA. ., QBI COVID-19 Research Group (QCRG), San Francisco, CA, 94158, USA. ., QBI COVID-19 Research Group (QCRG), San Francisco, CA, 94158, USA. .