2015 Protease inhibitors targeting coronavirus and filovirus entry

9 Pages·2015·1.25 MB·English

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Protease inhibitors targeting coronavirus and filovirus entry

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Yanchen Zhou a,b, Punitha Vedantham c, Kai Lu a, Juliet Agudelo a, Ricardo Carrion d, Jerritt W. Nunneley d,

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Dale Barnard e, Stefan Pöhlmann f, James H. McKerrow g,1, Adam R. Renslo c, Graham Simmons a,b,⇑

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a Blood Systems Research Institute, San Francisco, CA 94118, USA

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b Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94118, USA

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c Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA

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d Texas Biomedical Research Institute, San Antonio, TX 78227, USA

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e Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Science, Utah State University, Logan, UT 84322, USA

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f Infection Biology Unit, German Primate Center, 37077 Göttingen, Germany

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g Department of Pathology and Center for Discovery and Innovation in Parasitic Diseases, University of California, San Francisco, San Francisco, CA 94158, USA

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a r t i c l e
i n f o

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Article history:
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Received 28 October 2014
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Revised 14 January 2015
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Accepted 25 January 2015
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Available online xxxx

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Keywords:
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Vinylsulfones
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Coronavirus
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Filovirus
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Cathepsin
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a b s t r a c t

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In order to gain entry into cells, diverse viruses, including Ebola virus, SARS-coronavirus and the emerg-
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ing MERS-coronavirus, depend on activation of their envelope glycoproteins by host cell proteases. The
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respective enzymes are thus excellent targets for antiviral intervention. In cell culture, activation of Ebola
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virus, as well as SARS- and MERS-coronavirus can be accomplished by the endosomal cysteine proteases,
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cathepsin L (CTSL) and cathepsin B (CTSB). In addition, SARS- and MERS-coronavirus can use serine
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proteases localized at the cell surface, for their activation. However, it is currently unclear which prote-
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ase(s) facilitate viral spread in the infected host. We report here that the cysteine protease inhibitor
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K11777,
((2S)-N-[(1E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]-2-{[(E)-4-methylpiperazine-1-
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carbonyl]amino}-3-phenylpropanamide) and closely-related vinylsulfones act as broad-spectrum antiv-
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irals by targeting cathepsin-mediated cell entry. K11777 is already in advanced stages of development
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for a number of parasitic diseases, such as Chagas disease, and has proven to be safe and effective in a
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range of animal models. K11777 inhibition of SARS-CoV and Ebola virus entry was observed in the
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sub-nanomolar range. In order to assess, whether cysteine or serine proteases promote viral spread in
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the host, we compared the antiviral activity of an optimized K11777-derivative with that of camostat,
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an inhibitor of TMPRSS2 and related serine proteases. Employing a pathogenic animal model of SARS-
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CoV infection, we demonstrated that viral spread and pathogenesis of SARS-CoV is driven by serine rather
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than cysteine proteases and can be effectively prevented by camostat. Camostat has been clinically used
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to treat chronic pancreatitis, and thus represents an exciting potential therapeutic for respiratory coro-
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navirus infections. Our results indicate that camostat, or similar serine protease inhibitors, might be an
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effective option for treatment of SARS and potentially MERS, while vinyl sulfone-based inhibitors are
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excellent lead candidates for Ebola virus therapeutics.
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� 2015 Published by Elsevier B.V.
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1. Introduction

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Emerging viral diseases pose a unique risk to public health. Ebo-

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la virus, severe acute respiratory syndrome coronavirus (SARS-

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CoV) and members of the Henipavirus genus of paramyxoviruses

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are all highly pathogenic viruses that have arisen in the past

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40 years and caused, or threaten to cause, major outbreaks. New

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viral threats continue to emerge, most recently demonstrated by

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a novel beta-coronavirus, Middle East Respiratory Syndrome Coro-

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navirus (MERS-CoV), which was identified in 2012 (Zaki et al.,

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2012; Memish et al., 2013; de Groot et al., 2013). There are cur-

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rently no approved vaccines or therapeutics for many of the highly

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pathogenic viruses potentially dependent on cathepsins, including

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Ebola virus, Nipah virus (NiV), MERS-CoV and SARS-CoV. Broad-

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spectrum antiviral drugs, with overlapping therapeutic indications,

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would facilitate rapid responses to new or changing pandemic

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threats, potentially even without precise identification of the

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agent. Targeting host factors involved in viral entry provides an

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excellent avenue for such drug development, due to the limited

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number of pathways involved (Zhou et al., 2011).

http://dx.doi.org/10.1016/j.antiviral.2015.01.011
0166-3542/� 2015 Published by Elsevier B.V.

⇑ Corresponding author at: Blood Systems Research Institute, 270 Masonic
Avenue, San Francisco, CA 94118, USA. Tel.: [phone]; fax: [phone].
E-mail address: