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SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor.
Cell. 2020 04 16; 181(2):271-280.e8.Cell

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.

Links

Publisher Full Text
ncbi.nlm.nih.gov
linkinghub.elsevier.com
PMC Free PDF

Authors+Show Affiliations

Hoffmann M
Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, Göttingen, Germany. Electronic address: mhoffmann@dpz.eu.
Kleine-Weber H
Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, Göttingen, Germany; Faculty of Biology and Psychology, University Göttingen, Göttingen, Germany.
Schroeder S
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.
Krüger N
Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany; Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Hannover, Germany.
Herrler T
BG Unfallklinik Murnau, Murnau, Germany.
Erichsen S
Institute for Biomechanics, BG Unfallklinik Murnau, Murnau, Germany; Institute for Biomechanics, Paracelsus Medical University Salzburg, Salzburg, Austria.
Schiergens TS
Biobank of the Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.
Herrler G
Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany.
Wu NH
Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany.
Nitsche A
Robert Koch Institute, ZBS 1 Highly Pathogenic Viruses, WHO Collaborating Centre for Emerging Infections and Biological Threats, Berlin, Germany.
Müller MA
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.
Drosten C
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.
Pöhlmann S
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.

MeSH

Ammonium ChlorideAnimalsAntibodies, NeutralizingAntibodies, ViralBetacoronavirusCell LineCoronavirusCoronavirus InfectionsDrug DevelopmentGabexateHumansImmunization, PassiveLeucinePandemicsPeptidyl-Dipeptidase APneumonia, ViralProtease InhibitorsReceptors, VirusSARS VirusSerine EndopeptidasesSpike Glycoprotein, CoronavirusVesiculovirusVirus Internalization

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32142651

Clinical Trial Links

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Low-dose Hydroxychloroquine and Bromhexine: a Novel Regimen for COVID-19 Prophylaxis in Healthcare Professionals
Efficacy of Nafamostat in Covid-19 Patients (RACONA Study)
A Clinical Trial of Nebulized Surfactant for the Treatment of Moderate to Severe COVID-19
CORONA: A Study Using DeltaRex-G Gene Therapy for Symptomatic COVID-19
Detection Rate of SARS-CoV-2 in Male Genitourinary System and Its Impact on Male Reproductive Health.
Clinical Efficacy of Nafamostat Mesylate for COVID-19 Pneumonia
Hemostasis in COVID-19: an Adaptive Clinical Trial
The Use of Brazilian Green Propolis Extract (EPP-AF) in Patients Affected by COVID-19.
Camostat and Artemisia Annua vs Placebo in COVID-19 Outpatients

Citation

Hoffmann, Markus, et al. "SARS-CoV-2 Cell Entry Depends On ACE2 and TMPRSS2 and Is Blocked By a Clinically Proven Protease Inhibitor." Cell, vol. 181, no. 2, 2020, pp. 271-280.e8.
Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271-280.e8.
Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T. S., Herrler, G., Wu, N. H., Nitsche, A., Müller, M. A., Drosten, C., & Pöhlmann, S. (2020). SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell, 181(2), 271-e8. https://doi.org/10.1016/j.cell.2020.02.052
Hoffmann M, et al. SARS-CoV-2 Cell Entry Depends On ACE2 and TMPRSS2 and Is Blocked By a Clinically Proven Protease Inhibitor. Cell. 2020 04 16;181(2):271-280.e8. PubMed PMID: 32142651.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. AU - Hoffmann,Markus, AU - Kleine-Weber,Hannah, AU - Schroeder,Simon, AU - Krüger,Nadine, AU - Herrler,Tanja, AU - Erichsen,Sandra, AU - Schiergens,Tobias S, AU - Herrler,Georg, AU - Wu,Nai-Huei, AU - Nitsche,Andreas, AU - Müller,Marcel A, AU - Drosten,Christian, AU - Pöhlmann,Stefan, Y1 - 2020/03/05/ PY - 2020/02/06/received PY - 2020/02/13/revised PY - 2020/02/25/accepted PY - 2020/3/7/pubmed PY - 2020/4/24/medline PY - 2020/3/7/entrez KW - ACE2 KW - COVID-19 KW - SARS-CoV-2 KW - TMPRSS2 KW - coronavirus KW - entry KW - neutralization KW - priming KW - spike SP - 271 EP - 280.e8 JF - Cell JO - Cell VL - 181 IS - 2 N2 - 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. SN - 1097-4172 UR - https://www.unboundmedicine.com/medline/citation/32142651/full_citation L2 - https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(20)30229-4 DB - PRIME DP - Unbound Medicine ER -