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.
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 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 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 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  12  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-Ozturk  1  20  21 ,  Hao-Yuan Wang  1  2  4 ,  Raphael Trenker  1  2  22 ,  Janet M Young  23 ,  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 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
  • 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.
PMID: 32353859 DOI: 10.1038/s41586-020-2286-9
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.

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