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. 2020 Apr 30.
doi: 10.1038/s41586-020-2286-9. Online ahead of print.

A SARS-CoV-2 Protein Interaction Map Reveals Targets for Drug Repurposing

David E Gordon  1   2   3   4 Gwendolyn M Jang  1   2   3   4 Mehdi Bouhaddou  1   2   3   4 Jiewei Xu  1   2   3   4 Kirsten Obernier  1   2   3   4 Kris M White  5   6 Matthew J O'Meara  7 Veronica V Rezelj  8 Jeffrey Z Guo  1   2   3   4 Danielle L Swaney  1   2   3   4 Tia A Tummino  1   2   9 Ruth Huettenhain  1   2   3   4 Robyn M Kaake  1   2   3   4 Alicia L Richards  1   2   3   4 Beril Tutuncuoglu  1   2   3   4 Helene Foussard  1   2   3   4 Jyoti Batra  1   2   3   4 Kelsey Haas  1   2   3   4 Maya Modak  1   2   3   4 Minkyu Kim  1   2   3   4 Paige Haas  1   2   3   4 Benjamin J Polacco  1   2   3   4 Hannes Braberg  1   2   3   4 Jacqueline M Fabius  1   2   3   4 Manon Eckhardt  1   2   3   4 Margaret Soucheray  1   2   3   4 Melanie J Bennett  1   2   3   4 Merve Cakir  1   2   3   4 Michael J McGregor  1   2   3   4 Qiongyu Li  1   2   3   4 Bjoern Meyer  8 Ferdinand Roesch  8 Thomas Vallet  8 Alice Mac Kain  8 Lisa Miorin  5   6 Elena Moreno  5   6 Zun Zar Chi Naing  1   2   3   4 Yuan Zhou  1   2   3   4 Shiming Peng  1   2   9 Ying Shi  1   2   4   10 Ziyang Zhang  1   2   4   10 Wenqi Shen  1   2   4   10 Ilsa T Kirby  1   2   4   10 James E Melnyk  1   2   4   10 John S Chorba  1   2   4   10 Kevin Lou  1   2   4   10 Shizhong A Dai  1   2   4   10 Inigo Barrio-Hernandez  11 Danish Memon  11 Claudia Hernandez-Armenta  11 Jiankun Lyu  1   2   9 Christopher J P Mathy  1   2   12   13 Tina Perica  1   2   12 Kala B Pilla  1   2   12 Sai J Ganesan  1   2   12 Daniel J Saltzberg  1   2   12 Ramachandran Rakesh  1   2   12 Xi Liu  1   2   9 Sara B Rosenthal  14 Lorenzo Calviello  1   15 Srivats Venkataramanan  1   15 Jose Liboy-Lugo  1   15 Yizhu Lin  1   15 Xi-Ping Huang  16 YongFeng Liu  16 Stephanie A Wankowicz  1   2   10   17 Markus Bohn  1   2   9 Maliheh Safari  1   2   18 Fatima S Ugur  1   2   4   9 Cassandra Koh  8 Nastaran Sadat Savar  8 Quang Dinh Tran  8 Djoshkun Shengjuler  8 Sabrina J Fletcher  8 Michael C O'Neal  19 Yiming Cai  19 Jason C J Chang  19 David J Broadhurst  19 Saker Klippsten  19 Phillip P Sharp  4 Nicole A Wenzell  1   2   4 Duygu Kuzuoglu  1   2   4   20   21 Hao-Yuan Wang  1   2   4 Raphael Trenker  1   2   22 Janet M Young  23 Devin A Cavero  3   24 Joseph Hiatt  3   25   24 Theodore L Roth  3   25   24 Ujjwal Rathore  3   24 Advait Subramanian  1   2   24 Julia Noack  1   2   24 Mathieu Hubert  26 Robert M Stroud  1   2   18 Alan D Frankel  1   2   18 Oren S Rosenberg  1   2   18   27 Kliment A Verba  1   2   9 David A Agard  1   2   18 Melanie Ott  1   2   3   27 Michael Emerman  28 Natalia Jura  1   2   4   22 Mark von Zastrow  1   2   4   29 Eric Verdin  1   27   30 Alan Ashworth  1   2   20 Olivier Schwartz  26 Christophe d'Enfert  31 Shaeri Mukherjee  1   2   24 Matt Jacobson  1   2   9 Harmit S Malik  23 Danica G Fujimori  1   2   4   9 Trey Ideker  1   32 Charles S Craik  1   2   9   20 Stephen N Floor  1   15   20 James S Fraser  1   2   12 John D Gross  1   2   9 Andrej Sali  1   2   9   12 Bryan L Roth  16 Davide Ruggero  1   2   4   20   21 Jack Taunton  1   2   4 Tanja Kortemme  1   2   12   13 Pedro Beltrao  1   11 Marco Vignuzzi  33 Adolfo García-Sastre  34   35   36   37 Kevan M Shokat  38   39   40   41 Brian K Shoichet  42   43   44 Nevan J Krogan  45   46   47   48   49
Affiliations

A SARS-CoV-2 Protein Interaction Map Reveals Targets for Drug Repurposing

David E Gordon et al. Nature. .

Abstract

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.

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