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

David Gordon (1, 2, 3) , Gwendolyn Jang (1, 2, 3) , Mehdi Bouhaddou (1, 2, 3) , Jiewei Xu (1, 2, 3) , Kirsten Obernier (1, 2, 3) , Kris White (4) , Matthew O’meara (5) , Veronica Rezelj (6) , Jeffrey Guo (1, 2, 3) , Danielle Swaney (1, 2, 3) , Tia Tummino (1, 2) , Ruth Hüttenhain (1, 2, 3) , Robyn Kaake (1, 2, 3) , Alicia Richards (1, 2, 3) , Beril Tutuncuoglu (1, 2, 3) , Helene Foussard (1, 2, 3) , Jyoti Batra (1, 2, 3) , Kelsey Haas (1, 2, 3) , Maya Modak (1, 2, 3) , Minkyu Kim (1, 2, 3) , Paige Haas (1, 2, 3) , Benjamin Polacco (1, 2, 3) , Hannes Braberg (1, 2, 3) , Jacqueline Fabius (1, 2, 3) , Manon Eckhardt (1, 2, 3) , Margaret Soucheray (1, 2, 3) , Melanie Bennett (1, 2, 3) , Merve Cakir (1, 2, 3) , Michael Mcgregor (1, 2, 3) , Qiongyu Li (1, 2, 3) , Bjoern Meyer (6) , Ferdinand Roesch (6) , Thomas Vallet (6) , Alice Mac Kain (6) , Lisa Miorin (4) , Elena Moreno (4) , Zun Zar Chi Naing (1, 2, 3) , Yuan Zhou (1, 2, 3) , Shiming Peng (1, 2) , Ying Shi (1, 2) , Ziyang Zhang (1, 2) , Wenqi Shen (1, 2) , Ilsa Kirby (1, 2) , James Melnyk (1, 2) , John Chorba (1, 2) , Kevin Lou (1, 2) , Shizhong Dai (1, 2) , Inigo Barrio-Hernandez (7) , Danish Memon (7) , Claudia Hernandez-Armenta (7) , Jiankun Lyu (1, 2) , Christopher Mathy (1, 2) , Tina Perica (1, 2) , Kala Bharath Pilla (1, 2) , Sai Ganesan (1, 2) , Daniel Saltzberg (1, 2) , Ramachandran Rakesh (1, 2) , Xi Liu (1, 2) , Sara Rosenthal (8) , Lorenzo Calviello (1, 2) , Srivats Venkataramanan (1, 2) , Jose Liboy-Lugo (1, 2) , Yizhu Lin (1, 2) , Xi-Ping Huang (9) , Yongfeng Liu (9) , Stephanie Wankowicz (1, 2) , Markus Bohn (1, 2) , Maliheh Safari (1, 2) , Fatima Ugur (1, 2) , Cassandra Koh (6) , Nastaran Sadat Savar (6) , Quang Dinh Tran (6) , Djoshkun Shengjuler (6) , Sabrina Fletcher (6) , Michael O’neal (10) , Yiming Cai (10) , Jason Chang (10) , David Broadhurst (10) , Saker Klippsten (10) , Phillip Sharp (2) , Nicole Wenzell (1, 2) , Duygu Kuzuoglu-Ozturk (1, 2) , Hao-Yuan Wang (1, 2) , Raphael Trenker (1, 2) , Janet Young (11) , Devin Cavero (1, 3, 2) , Joseph Hiatt (1, 3, 2) , Theodore Roth (1, 3, 2) , Ujjwal Rathore (1, 3, 2) , Advait Subramanian (1, 2) , Julia Noack (1, 2) , Mathieu Hubert (12) , Robert Stroud (1, 2) , Alan Frankel (1, 2) , Oren Rosenberg (1, 2) , Kliment Verba (1, 2) , David Agard (1, 2) , Melanie Ott (1, 2, 3) , Michael Emerman (11) , Natalia Jura (1, 2) , Mark von Zastrow (1, 2) , Eric Verdin (1, 2, 13) , Alan Ashworth (1, 2) , Olivier Schwartz (12) , Christophe D’enfert (14) , Shaeri Mukherjee (1, 2) , Matt Jacobson (1, 2) , Harmit Malik (11) , Danica Fujimori (1, 2) , Trey Ideker (1, 8) , Charles Craik (1, 2) , Stephen Floor (1, 2) , James Fraser (1, 2) , John Gross (1, 2) , Andrej Sali (1, 2) , Bryan Roth (9) , Davide Ruggero (1, 2) , Jack Taunton (1, 2) , Tanja Kortemme (1, 2) , Pedro Beltrao (1, 7) , Marco Vignuzzi (6) , Adolfo García-Sastre (4) , Kevan Shokat (1, 2) , Brian Shoichet (1, 2) , Nevan Krogan (1, 2, 3, 4)

1 QCRG - QBI Coronavirus Research Group [San Francisco]
2 UC San Francisco - University of California [San Francisco]
3 Gladstone Institutes [San Francisco]
4 MSSM - Icahn School of Medicine at Mount Sinai [New York]
5 University of Michigan [Ann Arbor]
6 Populations virales et Pathogenèse - Viral Populations and Pathogenesis
7 EMBL-EBI - European Bioinformatics Institute [Hinxton]
8 UC San Diego - University of California [San Diego]
9 UNC - University of North Carolina [Chapel Hill]
10 Zoic Labs [Culver City, CA]
11 FHCRC - Fred Hutchinson Cancer Research Center [Seattle]
12 CNRS-UMR3569 - Virus et Immunité - Virus and immunity
13 Buck Institute for Research on Aging
14 IP - Institut Pasteur [Paris]

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.

Domaines: Virologie

David Gordon, Gwendolyn Jang, Mehdi Bouhaddou, Jiewei Xu, Kirsten Obernier, et al.. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature, 2020, 583 (7816), pp.459-468. ⟨10.1038/s41586-020-2286-9⟩. ⟨hal-04181569⟩