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Antiviral Res. 2015 Apr;116:76-84. doi: 10.1016/j.antiviral.2015.01.011. Epub 2015 Feb 7.

Protease inhibitors targeting coronavirus and filovirus entry.

Author information

1
Blood Systems Research Institute, San Francisco, CA 94118, USA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94118, USA.
2
Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
3
Blood Systems Research Institute, San Francisco, CA 94118, USA.
4
Texas Biomedical Research Institute, San Antonio, TX 78227, USA.
5
Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Science, Utah State University, Logan, UT 84322, USA.
6
Infection Biology Unit, German Primate Center, 37077 Göttingen, Germany.
7
Department of Pathology and Center for Discovery and Innovation in Parasitic Diseases, University of California, San Francisco, San Francisco, CA 94158, USA.
8
Blood Systems Research Institute, San Francisco, CA 94118, USA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94118, USA. Electronic address: gsimmons@bloodsystems.org.

Abstract

In order to gain entry into cells, diverse viruses, including Ebola virus, SARS-coronavirus and the emerging MERS-coronavirus, depend on activation of their envelope glycoproteins by host cell proteases. The respective enzymes are thus excellent targets for antiviral intervention. In cell culture, activation of Ebola virus, as well as SARS- and MERS-coronavirus can be accomplished by the endosomal cysteine proteases, cathepsin L (CTSL) and cathepsin B (CTSB). In addition, SARS- and MERS-coronavirus can use serine proteases localized at the cell surface, for their activation. However, it is currently unclear which protease(s) facilitate viral spread in the infected host. We report here that the cysteine protease inhibitor K11777, ((2S)-N-[(1E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]-2-{[(E)-4-methylpiperazine-1-carbonyl]amino}-3-phenylpropanamide) and closely-related vinylsulfones act as broad-spectrum antivirals by targeting cathepsin-mediated cell entry. K11777 is already in advanced stages of development for a number of parasitic diseases, such as Chagas disease, and has proven to be safe and effective in a range of animal models. K11777 inhibition of SARS-CoV and Ebola virus entry was observed in the sub-nanomolar range. In order to assess whether cysteine or serine proteases promote viral spread in the host, we compared the antiviral activity of an optimized K11777-derivative with that of camostat, an inhibitor of TMPRSS2 and related serine proteases. Employing a pathogenic animal model of SARS-CoV infection, we demonstrated that viral spread and pathogenesis of SARS-CoV is driven by serine rather than cysteine proteases and can be effectively prevented by camostat. Camostat has been clinically used to treat chronic pancreatitis, and thus represents an exciting potential therapeutic for respiratory coronavirus infections. Our results indicate that camostat, or similar serine protease inhibitors, might be an effective option for treatment of SARS and potentially MERS, while vinyl sulfone-based inhibitors are excellent lead candidates for Ebola virus therapeutics.

KEYWORDS:

Cathepsin; Coronavirus; Filovirus; Vinylsulfones

PMID:
25666761
PMCID:
PMC4774534
DOI:
10.1016/j.antiviral.2015.01.011
[Indexed for MEDLINE]
Free PMC Article

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