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.

Authors

Affiliations

¹ Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, Göttingen, Germany. Electronic address: mhoffmann@dpz.eu.
² Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, Göttingen, Germany; Faculty of Biology and Psychology, University Göttingen, Göttingen, Germany.
³ Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology, Berlin, Germany; German Centre for Infection Research, associated partner Charité, Berlin, Germany.
⁴ Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany; Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Hannover, Germany.
⁵ BG Unfallklinik Murnau, Murnau, Germany.
⁶ Institute for Biomechanics, BG Unfallklinik Murnau, Murnau, Germany; Institute for Biomechanics, Paracelsus Medical University Salzburg, Salzburg, Austria.
⁷ Biobank of the Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.
⁸ Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany.
⁹ Robert Koch Institute, ZBS 1 Highly Pathogenic Viruses, WHO Collaborating Centre for Emerging Infections and Biological Threats, Berlin, Germany.
¹⁰ Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology, Berlin, Germany; German Centre for Infection Research, associated partner Charité, Berlin, Germany; Martsinovsky Institute of Medical Parasitology, Tropical and Vector Borne Diseases, Sechenov University, Moscow, Russia.
¹¹ Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, Göttingen, Germany; Faculty of Biology and Psychology, University Göttingen, Göttingen, Germany. Electronic address: spoehlmann@dpz.eu.

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
Angiotensin-Converting Enzyme 2
Animals
Antibodies, Neutralizing / immunology
Antibodies, Viral / immunology
Betacoronavirus / chemistry
Betacoronavirus / genetics
Betacoronavirus / metabolism*
COVID-19
COVID-19 Serotherapy
Cell Line
Coronavirus / chemistry
Coronavirus / genetics
Coronavirus / physiology
Coronavirus Infections / drug therapy*
Coronavirus Infections / immunology
Coronavirus Infections / therapy
Drug Development
Esters
Gabexate / analogs & derivatives
Gabexate / pharmacology
Guanidines
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-CoV-2
Serine Endopeptidases / metabolism*
Severe acute respiratory syndrome-related coronavirus / physiology
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
Esters
Guanidines
Protease Inhibitors
Receptors, Virus
Spike Glycoprotein, Coronavirus
spike glycoprotein, SARS-CoV
Ammonium Chloride
camostat
Gabexate
Peptidyl-Dipeptidase A
ACE2 protein, human
Angiotensin-Converting Enzyme 2
Serine Endopeptidases
TMPRSS2 protein, human
Leucine

Grants and funding

German Research Foundation/International