Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry

J Virol. 2012 Jun;86(12):6537-45. doi: 10.1128/JVI.00094-12. Epub 2012 Apr 11.

Abstract

The type II transmembrane protease TMPRSS2 activates the spike (S) protein of severe acute respiratory syndrome coronavirus (SARS-CoV) on the cell surface following receptor binding during viral entry into cells. In the absence of TMPRSS2, SARS-CoV achieves cell entry via an endosomal pathway in which cathepsin L may play an important role, i.e., the activation of spike protein fusogenicity. This study shows that a commercial serine protease inhibitor (camostat) partially blocked infection by SARS-CoV and human coronavirus NL63 (HCoV-NL63) in HeLa cells expressing the receptor angiotensin-converting enzyme 2 (ACE2) and TMPRSS2. Simultaneous treatment of the cells with camostat and EST [(23,25)trans-epoxysuccinyl-L-leucylamindo-3-methylbutane ethyl ester], a cathepsin inhibitor, efficiently prevented both cell entry and the multistep growth of SARS-CoV in human Calu-3 airway epithelial cells. This efficient inhibition could be attributed to the dual blockade of entry from the cell surface and through the endosomal pathway. These observations suggest camostat as a candidate antiviral drug to prevent or depress TMPRSS2-dependent infection by SARS-CoV.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bronchi / cytology*
  • Bronchi / virology
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Down-Regulation / drug effects*
  • Epithelial Cells / drug effects
  • Epithelial Cells / virology*
  • Humans
  • SARS Virus / drug effects*
  • SARS Virus / physiology*
  • Serine Proteinase Inhibitors / pharmacology*
  • Severe Acute Respiratory Syndrome / drug therapy
  • Severe Acute Respiratory Syndrome / virology*
  • Virus Internalization / drug effects*

Substances

  • Cysteine Proteinase Inhibitors
  • Serine Proteinase Inhibitors