SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Cell. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052. Epub 2020 Mar 5.

Abstract

The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

Keywords: ACE2; COVID-19; SARS-CoV-2; TMPRSS2; coronavirus; entry; neutralization; priming; spike.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ammonium Chloride / pharmacology
  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / immunology
  • Betacoronavirus / chemistry
  • Betacoronavirus / genetics
  • Betacoronavirus / metabolism*
  • Cell Line
  • Coronavirus / chemistry
  • Coronavirus / genetics
  • Coronavirus / physiology
  • Coronavirus Infections / drug therapy*
  • Coronavirus Infections / immunology
  • Coronavirus Infections / therapy
  • Drug Development
  • Gabexate / analogs & derivatives
  • Gabexate / pharmacology
  • Humans
  • Immunization, Passive
  • Leucine / analogs & derivatives
  • Leucine / pharmacology
  • Pandemics
  • Peptidyl-Dipeptidase A / chemistry
  • Peptidyl-Dipeptidase A / metabolism*
  • Pneumonia, Viral / drug therapy*
  • Protease Inhibitors / pharmacology*
  • Receptors, Virus / chemistry
  • Receptors, Virus / metabolism
  • SARS Virus / physiology
  • Serine Endopeptidases / metabolism*
  • Spike Glycoprotein, Coronavirus / chemistry
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / metabolism*
  • Vesiculovirus / genetics
  • Virus Internalization / drug effects*

Substances

  • (3-ethoxycarbonyloxirane-2-carbonyl)leucine (3-methylbutyl) amide
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Protease Inhibitors
  • Receptors, Virus
  • Spike Glycoprotein, Coronavirus
  • spike glycoprotein, SARS-CoV
  • Ammonium Chloride
  • camostat
  • Gabexate
  • Peptidyl-Dipeptidase A
  • angiotensin converting enzyme 2
  • Serine Endopeptidases
  • TMPRSS2 protein, human
  • Leucine

Supplementary concepts

  • COVID-19
  • COVID-19 serotherapy
  • severe acute respiratory syndrome coronavirus 2