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

Author

Listed:
  • David E. Gordon

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Gwendolyn M. Jang

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Mehdi Bouhaddou

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Jiewei Xu

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Kirsten Obernier

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Kris M. White

    (Icahn School of Medicine at Mount Sinai
    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)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Danielle L. Swaney

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Tia A. Tummino

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Ruth Hüttenhain

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Robyn M. Kaake

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Alicia L. Richards

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Beril Tutuncuoglu

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Helene Foussard

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Jyoti Batra

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Kelsey Haas

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Maya Modak

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Minkyu Kim

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Paige Haas

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Benjamin J. Polacco

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Hannes Braberg

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Jacqueline M. Fabius

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Manon Eckhardt

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Margaret Soucheray

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Melanie J. Bennett

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Merve Cakir

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Michael J. McGregor

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Qiongyu Li

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • 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
    Icahn School of Medicine at Mount Sinai)

  • Elena Moreno

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Zun Zar Chi Naing

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Yuan Zhou

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Shiming Peng

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Ying Shi

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Ziyang Zhang

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Wenqi Shen

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Ilsa T. Kirby

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • James E. Melnyk

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • John S. Chorba

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Kevin Lou

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Shizhong A. Dai

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • 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)
    University of California San Francisco
    University of California San Francisco)

  • Christopher J. P. Mathy

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Tina Perica

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Kala Bharath Pilla

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Sai J. Ganesan

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Daniel J. Saltzberg

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Ramachandran Rakesh

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Xi Liu

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Sara B. Rosenthal

    (University of California San Diego)

  • Lorenzo Calviello

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco)

  • Srivats Venkataramanan

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco)

  • Jose Liboy-Lugo

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco)

  • Yizhu Lin

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco)

  • 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)
    University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Markus Bohn

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Maliheh Safari

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Fatima S. Ugur

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • 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)
    University of California San Francisco
    University of California San Francisco)

  • Duygu Kuzuoglu-Ozturk

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Hao-Yuan Wang

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Raphael Trenker

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Janet M. Young

    (Fred Hutchinson Cancer Research Center)

  • Devin A. Cavero

    (QBI COVID-19 Research Group (QCRG)
    J. David Gladstone Institutes
    University of California San Francisco)

  • Joseph Hiatt

    (QBI COVID-19 Research Group (QCRG)
    J. David Gladstone Institutes
    University of California San Francisco)

  • Theodore L. Roth

    (QBI COVID-19 Research Group (QCRG)
    J. David Gladstone Institutes
    University of California San Francisco
    University of California San Francisco)

  • Ujjwal Rathore

    (QBI COVID-19 Research Group (QCRG)
    J. David Gladstone Institutes
    University of California San Francisco)

  • Advait Subramanian

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Julia Noack

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Mathieu Hubert

    (Institut Pasteur)

  • Robert M. Stroud

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Alan D. Frankel

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Oren S. Rosenberg

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Kliment A. Verba

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • David A. Agard

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Melanie Ott

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Michael Emerman

    (Fred Hutchinson Cancer Research Center)

  • Natalia Jura

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Mark Zastrow

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Eric Verdin

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    Buck Institute for Research on Aging)

  • Alan Ashworth

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Olivier Schwartz

    (Institut Pasteur)

  • Christophe d’Enfert

    (Institut Pasteur)

  • Shaeri Mukherjee

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Matt Jacobson

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Harmit S. Malik

    (Fred Hutchinson Cancer Research Center)

  • Danica G. Fujimori

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Trey Ideker

    (QBI COVID-19 Research Group (QCRG)
    University of California San Diego)

  • Charles S. Craik

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Stephen N. Floor

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • James S. Fraser

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • John D. Gross

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Andrej Sali

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Bryan L. Roth

    (University of North Carolina at Chapel Hill School of Medicine)

  • Davide Ruggero

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Jack Taunton

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Tanja Kortemme

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Pedro Beltrao

    (QBI COVID-19 Research Group (QCRG)
    European Bioinformatics Institute, Wellcome Genome Campus)

  • Marco Vignuzzi

    (Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur)

  • Adolfo García-Sastre

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Kevan M. Shokat

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Brian K. Shoichet

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    University of California San Francisco)

  • Nevan J. Krogan

    (QBI COVID-19 Research Group (QCRG)
    University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

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.

Suggested Citation

  • 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 & , 2020. "A SARS-CoV-2 protein interaction map reveals targets for drug repurposing," Nature, Nature, vol. 583(7816), pages 459-468, July.
    • Handle: RePEc:nat:nature:v:583:y:2020:i:7816:d:10.1038_s41586-020-2286-9
    DOI: 10.1038/s41586-020-2286-9
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