title: Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry.
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.
authors.affiliation: Department of Virology III, National Institute of Infectious Diseases, Murayama Branch, Gakuen Musashi-Murayama, Tokyo, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kawase
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shirato
authors.forename: Lia
authors.initials: L
authors.lastname: van der Hoek
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Taguchi
authors.forename: Shutoku
authors.initials: S
authors.lastname: Matsuyama
mesh_terms: D001980:Bronchi / Q000166:cytology* / Q000821:virology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects / Q000821:virology*; D006801:Humans; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects* / Q000502:physiology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D045169:Severe Acute Respiratory Syndrome / Q000188:drug therapy / Q000821:virology*; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D015842:Serine Proteinase Inhibitors