2. Academic Validation
  3. TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells

TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells

  • Life Sci Alliance. 2020 Jul 23;3(9):e202000786. doi: 10.26508/lsa.202000786.
Dorothea Bestle 1,  Miriam Ruth Heindl 1,  Hannah Limburg 1,  Thuy Van Lam van 2,  Oliver Pilgram 2,  Hong Moulton 3,  David A Stein 3,  Kornelia Hardes 2 4,  Markus Eickmann 1 5,  Olga Dolnik 1 5,  Cornelius Rohde 1 5,  Hans-Dieter Klenk 1,  Wolfgang Garten 1,  Torsten Steinmetzer 2,  Eva Böttcher-Friebertshäuser 6
Affiliations

Affiliations

  • 1 Institute of Virology, Philipps-University, Marburg, Germany.
  • 2 Institute of Pharmaceutical Chemistry, Philipps-University, Marburg, Germany.
  • 3 Department of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR, USA.
  • 4 Fraunhofer Institute for Molecular Biology and Applied Ecology, Gießen, Germany.
  • 5 German Center for Infection Research (DZIF), Marburg-Gießen-Langen Site, Emerging Infections Unit, Philipps-University, Marburg, Germany.
  • 6 Institute of Virology, Philipps-University, Marburg, Germany friebertshaeuser@staff.uni-marburg.de.
PMID: 32703818 DOI: 10.26508/lsa.202000786
Abstract

The novel emerged SARS-CoV-2 has rapidly spread around the world causing acute Infection of the respiratory tract (COVID-19) that can result in severe disease and lethality. For SARS-CoV-2 to enter cells, its surface glycoprotein spike (S) must be cleaved at two different sites by host cell proteases, which therefore represent potential drug targets. In the present study, we show that S can be cleaved by the proprotein convertase Furin at the S1/S2 site and the transmembrane serine protease 2 (TMPRSS2) at the S2' site. We demonstrate that TMPRSS2 is essential for activation of SARS-CoV-2 S in Calu-3 human airway epithelial cells through antisense-mediated knockdown of TMPRSS2 expression. Furthermore, SARS-CoV-2 replication was also strongly inhibited by the synthetic Furin inhibitor MI-1851 in human airway cells. In contrast, inhibition of endosomal cathepsins by E64d did not affect virus replication. Combining various TMPRSS2 inhibitors with Furin inhibitor MI-1851 produced more potent Antiviral activity against SARS-CoV-2 than an equimolar amount of any single serine protease inhibitor. Therefore, this approach has considerable therapeutic potential for treatment of COVID-19.

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