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Experimental Therapeutics

A Cysteine Protease Inhibitor Rescues Mice from a Lethal Cryptosporidium parvum Infection

Momar Ndao, Milli Nath-Chowdhury, Mohammed Sajid, Victoria Marcus, Susan T. Mashiyama, Judy Sakanari, Eric Chow, Zachary Mackey, Kirkwood M. Land, Matthew P. Jacobson, Chakrapani Kalyanaraman, James H. McKerrow, Michael J. Arrowood, Conor R. Caffrey
Momar Ndao
National Reference Centre for Parasitology, Research Institute of the McGill University Health Center, Montreal, Canadaa
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Milli Nath-Chowdhury
National Reference Centre for Parasitology, Research Institute of the McGill University Health Center, Montreal, Canadaa
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Mohammed Sajid
Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, California, USAb
Leiden University Medical Center, Leiden, Netherlandsc
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Victoria Marcus
Department of Pathology, McGill University Health Centre, Montreal General Hospital, Montreal, Canadad
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Susan T. Mashiyama
Bioengineering and Therapeutic Sciences,g University of California, San Francisco, San Francisco, California, USA
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Judy Sakanari
Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, California, USAb
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Eric Chow
Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, California, USAb
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Zachary Mackey
Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, California, USAb
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Kirkwood M. Land
Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, California, USAb
Department of Biological Sciences, University of the Pacific, Stockton, California, USAe
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Matthew P. Jacobson
Departments of Pharmaceutical Sciences, University of California, San Francisco, San Francisco, California, USAf
Bioengineering and Therapeutic Sciences,g University of California, San Francisco, San Francisco, California, USA
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Chakrapani Kalyanaraman
Departments of Pharmaceutical Sciences, University of California, San Francisco, San Francisco, California, USAf
Bioengineering and Therapeutic Sciences,g University of California, San Francisco, San Francisco, California, USA
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James H. McKerrow
Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, California, USAb
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Michael J. Arrowood
Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USAh
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Conor R. Caffrey
Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, California, USAb
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DOI: 10.1128/AAC.00734-13
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ABSTRACT

Cryptosporidiosis, caused by the protozoan parasite Cryptosporidium parvum, can stunt infant growth and can be lethal in immunocompromised individuals. The most widely used drugs for treating cryptosporidiosis are nitazoxanide and paromomycin, although both exhibit limited efficacy. To investigate an alternative approach to therapy, we demonstrate that the clan CA cysteine protease inhibitor N-methyl piperazine-Phe-homoPhe-vinylsulfone phenyl (K11777) inhibits C. parvum growth in mammalian cell lines in a concentration-dependent manner. Further, using the C57BL/6 gamma interferon receptor knockout (IFN-γR-KO) mouse model, which is highly susceptible to C. parvum, oral or intraperitoneal treatment with K11777 for 10 days rescued mice from otherwise lethal infections. Histologic examination of untreated mice showed intestinal inflammation, villous blunting, and abundant intracellular parasite stages. In contrast, K11777-treated mice (210 mg/kg of body weight/day) showed only minimal inflammation and no epithelial changes. Three putative protease targets (termed cryptopains 1 to 3, or CpaCATL-1, -2, and -3) were identified in the C. parvum genome, but only two are transcribed in infected mammals. A homology model predicted that K11777 would bind to cryptopain 1. Recombinant enzymatically active cryptopain 1 was successfully targeted by K11777 in a competition assay with a labeled active-site-directed probe. K11777 exhibited no toxicity in vitro and in vivo, and surviving animals remained free of parasites 3 weeks after treatment. The discovery that a cysteine protease inhibitor provides potent anticryptosporidial activity in an animal model of infection encourages the investigation and development of this biocide class as a new, and urgently needed, chemotherapy for cryptosporidiosis.

FOOTNOTES

    • Received 12 April 2013.
    • Returned for modification 27 May 2013.
    • Accepted 16 September 2013.
    • Accepted manuscript posted online 23 September 2013.
  • Supplemental material for this article may be found at http://dx.doi.org/10.1128/AAC.00734-13.

  • Copyright © 2013, American Society for Microbiology. All Rights Reserved.
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A Cysteine Protease Inhibitor Rescues Mice from a Lethal Cryptosporidium parvum Infection
Momar Ndao, Milli Nath-Chowdhury, Mohammed Sajid, Victoria Marcus, Susan T. Mashiyama, Judy Sakanari, Eric Chow, Zachary Mackey, Kirkwood M. Land, Matthew P. Jacobson, Chakrapani Kalyanaraman, James H. McKerrow, Michael J. Arrowood, Conor R. Caffrey
Antimicrobial Agents and Chemotherapy Nov 2013, 57 (12) 6063-6073; DOI: 10.1128/AAC.00734-13

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A Cysteine Protease Inhibitor Rescues Mice from a Lethal Cryptosporidium parvum Infection
Momar Ndao, Milli Nath-Chowdhury, Mohammed Sajid, Victoria Marcus, Susan T. Mashiyama, Judy Sakanari, Eric Chow, Zachary Mackey, Kirkwood M. Land, Matthew P. Jacobson, Chakrapani Kalyanaraman, James H. McKerrow, Michael J. Arrowood, Conor R. Caffrey
Antimicrobial Agents and Chemotherapy Nov 2013, 57 (12) 6063-6073; DOI: 10.1128/AAC.00734-13
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