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 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 García-Sastre; Kevan M Shokat; Brian K Shoichet; Nevan J Krogan

doi:10.1038/s41586-020-2286-9

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

Nature. 2020 Jul;583(7816):459-468. doi: 10.1038/s41586-020-2286-9. Epub 2020 Apr 30.

Authors

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 Hüttenhain^{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 Meyer⁸, Ferdinand Roesch⁸, Thomas Vallet⁸, Alice Mac Kain⁸, 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-Hernandez¹¹, Danish Memon¹¹, Claudia Hernandez-Armenta¹¹, Jiankun Lyu^{1

2

9}, Christopher J P Mathy^{1

2

12

13}, Tina Perica^{1

2

12}, Kala Bharath 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 Rosenthal¹⁴, Lorenzo Calviello^{1

15}, Srivats Venkataramanan^{1

15}, Jose Liboy-Lugo^{1

15}, Yizhu Lin^{1

15}, Xi-Ping Huang¹⁶, YongFeng Liu¹⁶, Stephanie A Wankowicz^{1

2

12

17}, Markus Bohn^{1

2

9}, Maliheh Safari^{1

2

18}, Fatima S Ugur^{1

2

4

9}, Cassandra Koh⁸, Nastaran Sadat Savar⁸, Quang Dinh Tran⁸, Djoshkun Shengjuler⁸, Sabrina J Fletcher⁸, Michael C O'Neal¹⁹, Yiming Cai¹⁹, Jason C J Chang¹⁹, David J Broadhurst¹⁹, Saker Klippsten¹⁹, Phillip P Sharp⁴, Nicole A Wenzell^{1

2

4}, Duygu Kuzuoglu-Ozturk^{1

20

21}, Hao-Yuan Wang^{1

2

4}, Raphael Trenker^{1

2

22}, Janet M Young²³, Devin A Cavero^{1

3

24}, Joseph Hiatt^{1

3

25}, Theodore L Roth^{1

3

24

25}, Ujjwal Rathore^{1

3

24}, Advait Subramanian^{1

2

24}, Julia Noack^{1

2

24}, Mathieu Hubert²⁶, 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 Emerman²⁸, Natalia Jura^{1

2

4

22}, Mark von Zastrow^{1

2

4

29}, Eric Verdin^{1

27

30}, Alan Ashworth^{1

2

20}, Olivier Schwartz²⁶, Christophe d'Enfert³¹, Shaeri Mukherjee^{1

2

24}, Matt Jacobson^{1

2

9}, Harmit S Malik²³, 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 Roth¹⁶, Davide Ruggero^{1

2

4

20

21}, Jack Taunton^{1

2

4}, Tanja Kortemme^{1

2

12

13}, Pedro Beltrao^{1

11}, Marco Vignuzzi³³, 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

¹ QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA.
² Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
³ J. David Gladstone Institutes, San Francisco, CA, USA.
⁴ Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
⁵ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
⁸ Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur, Paris, France.
⁹ Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
¹⁰ Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA, USA.
¹¹ European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, UK.
¹² Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
¹³ The UC Berkeley-UCSF Graduate Program in Bioengineering, University of California San Francisco, San Francisco, CA, USA.
¹⁴ Center for Computational Biology and Bioinformatics, Department of Medicine, University of California San Diego, San Diego, CA, USA.
¹⁵ Department of Cell and Tissue Biology, University of California San Francisco, San Francisco, CA, USA.
¹⁶ Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
¹⁷ Biophysics Graduate Program, University of California San Francisco, San Francisco, CA, USA.
¹⁸ Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA.
¹⁹ Zoic Labs, Culver City, CA, USA.
²⁰ Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
²¹ Department of Urology, University of California San Francisco, San Francisco, CA, USA.
²² Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
²³ Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²⁴ George William Hooper Foundation, Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA.
²⁵ Medical Scientist Training Program, University of California San Francisco, San Francisco, CA, USA.
²⁶ Virus and Immunity Unit, Institut Pasteur, Paris, France.
²⁷ Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
²⁸ Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²⁹ Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA.
³⁰ Buck Institute for Research on Aging, Novato, CA, USA.
³¹ Direction Scientifique, Institut Pasteur, Paris, France.
³² Division of Genetics, Department of Medicine, University of California San Diego, San Diego, CA, USA.
³³ Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur, Paris, France. [email protected].
³⁴ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
³⁵ Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
³⁶ Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
³⁷ The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
³⁸ QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA. [email protected].
³⁹ Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA. [email protected].
⁴⁰ Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA. [email protected].
⁴¹ Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA, USA. [email protected].
⁴² QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA. [email protected].
⁴³ Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA. [email protected].
⁴⁴ Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA. [email protected].
⁴⁵ QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA. [email protected].
⁴⁶ Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA. [email protected].
⁴⁷ J. David Gladstone Institutes, San Francisco, CA, USA. [email protected].
⁴⁸ Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA. [email protected].
⁴⁹ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].

^# Contributed equally.

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 disruption^1,2. 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antiviral Agents / classification
Antiviral Agents / pharmacology
Betacoronavirus / drug effects*
Betacoronavirus / genetics
Betacoronavirus / metabolism
Betacoronavirus / pathogenicity
COVID-19
COVID-19 Drug Treatment
Chlorocebus aethiops
Cloning, Molecular
Coronavirus Infections / drug therapy*
Coronavirus Infections / immunology
Coronavirus Infections / metabolism*
Coronavirus Infections / virology
Drug Evaluation, Preclinical
Drug Repositioning*
HEK293 Cells
Host-Pathogen Interactions / drug effects
Humans
Immunity, Innate
Mass Spectrometry
Molecular Targeted Therapy*
Pandemics
Pneumonia, Viral / drug therapy*
Pneumonia, Viral / immunology
Pneumonia, Viral / metabolism*
Pneumonia, Viral / virology
Protein Binding
Protein Biosynthesis / drug effects
Protein Domains
Protein Interaction Mapping
Protein Interaction Maps*
Receptors, sigma / metabolism
SARS-CoV-2
SKP Cullin F-Box Protein Ligases / metabolism
Vero Cells
Viral Proteins / genetics
Viral Proteins / metabolism*

Substances

Antiviral Agents
Receptors, sigma
Viral Proteins
SKP Cullin F-Box Protein Ligases

Abstract

Publication types

MeSH terms

Substances

Grants and funding