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

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

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

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 Hüttenhain, 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 Bharath 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-Ozturk, 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 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 García-Sastre (), Kevan M. Shokat (), Brian K. Shoichet () and Nevan J. Krogan ()
Additional contact information
David E. Gordon: QBI COVID-19 Research Group (QCRG)
Gwendolyn M. Jang: QBI COVID-19 Research Group (QCRG)
Mehdi Bouhaddou: QBI COVID-19 Research Group (QCRG)
Jiewei Xu: QBI COVID-19 Research Group (QCRG)
Kirsten Obernier: QBI COVID-19 Research Group (QCRG)
Kris M. White: Icahn School of Medicine at Mount Sinai
Matthew J. O’Meara: University of Michigan
Veronica V. Rezelj: Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur
Jeffrey Z. Guo: QBI COVID-19 Research Group (QCRG)
Danielle L. Swaney: QBI COVID-19 Research Group (QCRG)
Tia A. Tummino: QBI COVID-19 Research Group (QCRG)
Ruth Hüttenhain: QBI COVID-19 Research Group (QCRG)
Robyn M. Kaake: QBI COVID-19 Research Group (QCRG)
Alicia L. Richards: QBI COVID-19 Research Group (QCRG)
Beril Tutuncuoglu: QBI COVID-19 Research Group (QCRG)
Helene Foussard: QBI COVID-19 Research Group (QCRG)
Jyoti Batra: QBI COVID-19 Research Group (QCRG)
Kelsey Haas: QBI COVID-19 Research Group (QCRG)
Maya Modak: QBI COVID-19 Research Group (QCRG)
Minkyu Kim: QBI COVID-19 Research Group (QCRG)
Paige Haas: QBI COVID-19 Research Group (QCRG)
Benjamin J. Polacco: QBI COVID-19 Research Group (QCRG)
Hannes Braberg: QBI COVID-19 Research Group (QCRG)
Jacqueline M. Fabius: QBI COVID-19 Research Group (QCRG)
Manon Eckhardt: QBI COVID-19 Research Group (QCRG)
Margaret Soucheray: QBI COVID-19 Research Group (QCRG)
Melanie J. Bennett: QBI COVID-19 Research Group (QCRG)
Merve Cakir: QBI COVID-19 Research Group (QCRG)
Michael J. McGregor: QBI COVID-19 Research Group (QCRG)
Qiongyu Li: QBI COVID-19 Research Group (QCRG)
Bjoern Meyer: Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur
Ferdinand Roesch: Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur
Thomas Vallet: Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur
Alice Mac Kain: Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur
Lisa Miorin: Icahn School of Medicine at Mount Sinai
Elena Moreno: Icahn School of Medicine at Mount Sinai
Zun Zar Chi Naing: QBI COVID-19 Research Group (QCRG)
Yuan Zhou: QBI COVID-19 Research Group (QCRG)
Shiming Peng: QBI COVID-19 Research Group (QCRG)
Ying Shi: QBI COVID-19 Research Group (QCRG)
Ziyang Zhang: QBI COVID-19 Research Group (QCRG)
Wenqi Shen: QBI COVID-19 Research Group (QCRG)
Ilsa T. Kirby: QBI COVID-19 Research Group (QCRG)
James E. Melnyk: QBI COVID-19 Research Group (QCRG)
John S. Chorba: QBI COVID-19 Research Group (QCRG)
Kevin Lou: QBI COVID-19 Research Group (QCRG)
Shizhong A. Dai: QBI COVID-19 Research Group (QCRG)
Inigo Barrio-Hernandez: European Bioinformatics Institute, Wellcome Genome Campus
Danish Memon: European Bioinformatics Institute, Wellcome Genome Campus
Claudia Hernandez-Armenta: European Bioinformatics Institute, Wellcome Genome Campus
Jiankun Lyu: QBI COVID-19 Research Group (QCRG)
Christopher J. P. Mathy: QBI COVID-19 Research Group (QCRG)
Tina Perica: QBI COVID-19 Research Group (QCRG)
Kala Bharath Pilla: QBI COVID-19 Research Group (QCRG)
Sai J. Ganesan: QBI COVID-19 Research Group (QCRG)
Daniel J. Saltzberg: QBI COVID-19 Research Group (QCRG)
Ramachandran Rakesh: QBI COVID-19 Research Group (QCRG)
Xi Liu: QBI COVID-19 Research Group (QCRG)
Sara B. Rosenthal: University of California San Diego
Lorenzo Calviello: QBI COVID-19 Research Group (QCRG)
Srivats Venkataramanan: QBI COVID-19 Research Group (QCRG)
Jose Liboy-Lugo: QBI COVID-19 Research Group (QCRG)
Yizhu Lin: QBI COVID-19 Research Group (QCRG)
Xi-Ping Huang: University of North Carolina at Chapel Hill School of Medicine
YongFeng Liu: University of North Carolina at Chapel Hill School of Medicine
Stephanie A. Wankowicz: QBI COVID-19 Research Group (QCRG)
Markus Bohn: QBI COVID-19 Research Group (QCRG)
Maliheh Safari: QBI COVID-19 Research Group (QCRG)
Fatima S. Ugur: QBI COVID-19 Research Group (QCRG)
Cassandra Koh: Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur
Nastaran Sadat Savar: Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur
Quang Dinh Tran: Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur
Djoshkun Shengjuler: Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur
Sabrina J. Fletcher: Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur
Michael C. O’Neal: Zoic Labs
Yiming Cai: Zoic Labs
Jason C. J. Chang: Zoic Labs
David J. Broadhurst: Zoic Labs
Saker Klippsten: Zoic Labs
Phillip P. Sharp: University of California San Francisco
Nicole A. Wenzell: QBI COVID-19 Research Group (QCRG)
Duygu Kuzuoglu-Ozturk: QBI COVID-19 Research Group (QCRG)
Hao-Yuan Wang: QBI COVID-19 Research Group (QCRG)
Raphael Trenker: QBI COVID-19 Research Group (QCRG)
Janet M. Young: Fred Hutchinson Cancer Research Center
Devin A. Cavero: QBI COVID-19 Research Group (QCRG)
Joseph Hiatt: QBI COVID-19 Research Group (QCRG)
Theodore L. Roth: QBI COVID-19 Research Group (QCRG)
Ujjwal Rathore: QBI COVID-19 Research Group (QCRG)
Advait Subramanian: QBI COVID-19 Research Group (QCRG)
Julia Noack: QBI COVID-19 Research Group (QCRG)
Mathieu Hubert: Institut Pasteur
Robert M. Stroud: QBI COVID-19 Research Group (QCRG)
Alan D. Frankel: QBI COVID-19 Research Group (QCRG)
Oren S. Rosenberg: QBI COVID-19 Research Group (QCRG)
Kliment A. Verba: QBI COVID-19 Research Group (QCRG)
David A. Agard: QBI COVID-19 Research Group (QCRG)
Melanie Ott: QBI COVID-19 Research Group (QCRG)
Michael Emerman: Fred Hutchinson Cancer Research Center
Natalia Jura: QBI COVID-19 Research Group (QCRG)
Mark Zastrow: QBI COVID-19 Research Group (QCRG)
Eric Verdin: QBI COVID-19 Research Group (QCRG)
Alan Ashworth: QBI COVID-19 Research Group (QCRG)
Olivier Schwartz: Institut Pasteur
Christophe d’Enfert: Institut Pasteur
Shaeri Mukherjee: QBI COVID-19 Research Group (QCRG)
Matt Jacobson: QBI COVID-19 Research Group (QCRG)
Harmit S. Malik: Fred Hutchinson Cancer Research Center
Danica G. Fujimori: QBI COVID-19 Research Group (QCRG)
Trey Ideker: QBI COVID-19 Research Group (QCRG)
Charles S. Craik: QBI COVID-19 Research Group (QCRG)
Stephen N. Floor: QBI COVID-19 Research Group (QCRG)
James S. Fraser: QBI COVID-19 Research Group (QCRG)
John D. Gross: QBI COVID-19 Research Group (QCRG)
Andrej Sali: QBI COVID-19 Research Group (QCRG)
Bryan L. Roth: University of North Carolina at Chapel Hill School of Medicine
Davide Ruggero: QBI COVID-19 Research Group (QCRG)
Jack Taunton: QBI COVID-19 Research Group (QCRG)
Tanja Kortemme: QBI COVID-19 Research Group (QCRG)
Pedro Beltrao: QBI COVID-19 Research Group (QCRG)
Marco Vignuzzi: Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur
Adolfo García-Sastre: Icahn School of Medicine at Mount Sinai
Kevan M. Shokat: QBI COVID-19 Research Group (QCRG)
Brian K. Shoichet: QBI COVID-19 Research Group (QCRG)
Nevan J. Krogan: QBI COVID-19 Research Group (QCRG)

Nature, 2020, vol. 583, issue 7816, 459-468

Abstract: Abstract A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein–protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 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.

Date: 2020
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DOI: 10.1038/s41586-020-2286-9

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