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.

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.

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
  • 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
  • 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

Supplementary concepts

  • COVID-19
  • COVID-19 drug treatment
  • severe acute respiratory syndrome coronavirus 2