CovidV1, Main, Exploration, bibRecord, 000818

A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis

Identifieur interne : 000818 ( Main/Exploration ); précédent : 000817; suivant : 000819

A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis

Auteurs : Ujjini H. Manjunatha ; Sumiti Vinayak [États-Unis] ; Jennifer A. Zambriski [États-Unis] ; Alexander T. Chao ; Tracy Sy [États-Unis] ; Christian G. Noble ; Ghislain M. C. Bonamy ; Ravinder R. Kondreddi ; Bin Zou ; Peter Gedeck ; Carrie F. Brooks [États-Unis] ; Gillian T. Herbert [États-Unis] ; Adam Sateriale [États-Unis] ; Jayesh Tandel [États-Unis] ; Susan Noh [États-Unis] ; Suresh B. Lakshminarayana ; Siau H. Lim ; Laura B. Goodman [États-Unis] ; Christophe Bodenreider ; Gu Feng ; Lijun Zhang [République populaire de Chine] ; Francesca Blasco ; Juergen Wagner ; F. Joel Leong ; Boris Striepen [États-Unis] ; Thierry T. Diagana

Source :

Nature [ 0028-0836 ] ; 2017.

RBID : PMC:5473467

Abstract

Diarrheal disease is responsible for 8.6% of global child mortality. Recent epidemiological studies found the protozoan parasite Cryptosporidium to be a leading cause of pediatric diarrhea with particularly grave impact on infants and immunocompromised individuals. There is neither a vaccine nor effective treatment. We establish a drug discovery process built on scalable phenotypic assays and mouse models that takes advantage of transgenic parasites. Screening a library of compounds with anti-parasitic activity we identified pyrazolopyridines as inhibitors of Cryptosporidium parvum and C. hominis. Oral treatment with the pyrazolopyridine KDU731 results in potent reduction in intestinal infection of immunocompromised mice. Treatment also leads to rapid resolution of diarrhea and dehydration in neonatal calves, a clinical model of cryptosporidiosis that closely resembles human infection. Our results suggest the Cryptosporidium lipid kinase PI(4)K as a target for pyrazolopyridines and warrant further preclinical evaluation of KDU731 as a drug candidate for the treatment of cryptosporidiosis.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473467

DOI: 10.1038/nature22337
PubMed: 28562588
PubMed Central: 5473467

Affiliations:

Le document en format XML

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 PI(4)K inhibitor is a drug candidate for cryptosporidiosis</title>
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<author><name sortKey="Feng, Gu" sort="Feng, Gu" uniqKey="Feng G" first="Gu" last="Feng">Gu Feng</name>
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<author><name sortKey="Zhang, Lijun" sort="Zhang, Lijun" uniqKey="Zhang L" first="Lijun" last="Zhang">Lijun Zhang</name>
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<author><name sortKey="Blasco, Francesca" sort="Blasco, Francesca" uniqKey="Blasco F" first="Francesca" last="Blasco">Francesca Blasco</name>
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<author><name sortKey="Leong, F Joel" sort="Leong, F Joel" uniqKey="Leong F" first="F. Joel" last="Leong">F. Joel Leong</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A <italic>Cryptosporidium</italic>
 PI(4)K inhibitor is a drug candidate for cryptosporidiosis</title>
<author><name sortKey="Manjunatha, Ujjini H" sort="Manjunatha, Ujjini H" uniqKey="Manjunatha U" first="Ujjini H." last="Manjunatha">Ujjini H. Manjunatha</name>
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<wicri:noCountry code="subfield">Singapore 138670</wicri:noCountry>
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</author>
<author><name sortKey="Vinayak, Sumiti" sort="Vinayak, Sumiti" uniqKey="Vinayak S" first="Sumiti" last="Vinayak">Sumiti Vinayak</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA</wicri:regionArea>
<wicri:noRegion>GA</wicri:noRegion>
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<author><name sortKey="Zambriski, Jennifer A" sort="Zambriski, Jennifer A" uniqKey="Zambriski J" first="Jennifer A." last="Zambriski">Jennifer A. Zambriski</name>
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<author><name sortKey="Chao, Alexander T" sort="Chao, Alexander T" uniqKey="Chao A" first="Alexander T." last="Chao">Alexander T. Chao</name>
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<author><name sortKey="Sy, Tracy" sort="Sy, Tracy" uniqKey="Sy T" first="Tracy" last="Sy">Tracy Sy</name>
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<author><name sortKey="Noble, Christian G" sort="Noble, Christian G" uniqKey="Noble C" first="Christian G." last="Noble">Christian G. Noble</name>
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<wicri:noCountry code="subfield">Singapore 138670</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Bonamy, Ghislain M C" sort="Bonamy, Ghislain M C" uniqKey="Bonamy G" first="Ghislain M. C." last="Bonamy">Ghislain M. C. Bonamy</name>
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<author><name sortKey="Kondreddi, Ravinder R" sort="Kondreddi, Ravinder R" uniqKey="Kondreddi R" first="Ravinder R." last="Kondreddi">Ravinder R. Kondreddi</name>
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</affiliation>
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<author><name sortKey="Zou, Bin" sort="Zou, Bin" uniqKey="Zou B" first="Bin" last="Zou">Bin Zou</name>
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<wicri:noCountry code="subfield">Singapore 138670</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Gedeck, Peter" sort="Gedeck, Peter" uniqKey="Gedeck P" first="Peter" last="Gedeck">Peter Gedeck</name>
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<wicri:noCountry code="subfield">Singapore 138670</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Brooks, Carrie F" sort="Brooks, Carrie F" uniqKey="Brooks C" first="Carrie F." last="Brooks">Carrie F. Brooks</name>
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<author><name sortKey="Herbert, Gillian T" sort="Herbert, Gillian T" uniqKey="Herbert G" first="Gillian T." last="Herbert">Gillian T. Herbert</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA</wicri:regionArea>
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<author><name sortKey="Sateriale, Adam" sort="Sateriale, Adam" uniqKey="Sateriale A" first="Adam" last="Sateriale">Adam Sateriale</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA</wicri:regionArea>
<wicri:noRegion>GA</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Tandel, Jayesh" sort="Tandel, Jayesh" uniqKey="Tandel J" first="Jayesh" last="Tandel">Jayesh Tandel</name>
<affiliation wicri:level="1"><nlm:aff id="A4">Department of Cellular Biology, University of Georgia, Athens, GA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Cellular Biology, University of Georgia, Athens, GA</wicri:regionArea>
<wicri:noRegion>GA</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Noh, Susan" sort="Noh, Susan" uniqKey="Noh S" first="Susan" last="Noh">Susan Noh</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Washington State University, College of Veterinary Medicine, Paul G. Allen School for Global Animal Health, Pullman, WA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Washington State University, College of Veterinary Medicine, Paul G. Allen School for Global Animal Health, Pullman, WA</wicri:regionArea>
<wicri:noRegion>WA</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A5">USDA-Agricultural Research Service, Animal Disease Research Unit and Washington State University, Department of Veterinary Microbiology and Pathology, Washington Animal Disease Diagnostic Laboratory, Pullman, WA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>USDA-Agricultural Research Service, Animal Disease Research Unit and Washington State University, Department of Veterinary Microbiology and Pathology, Washington Animal Disease Diagnostic Laboratory, Pullman, WA</wicri:regionArea>
<wicri:noRegion>WA</wicri:noRegion>
</affiliation>
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<author><name sortKey="Lakshminarayana, Suresh B" sort="Lakshminarayana, Suresh B" uniqKey="Lakshminarayana S" first="Suresh B." last="Lakshminarayana">Suresh B. Lakshminarayana</name>
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<wicri:noCountry code="subfield">Singapore 138670</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Lim, Siau H" sort="Lim, Siau H" uniqKey="Lim S" first="Siau H." last="Lim">Siau H. Lim</name>
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<wicri:noCountry code="subfield">Singapore 138670</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Goodman, Laura B" sort="Goodman, Laura B" uniqKey="Goodman L" first="Laura B." last="Goodman">Laura B. Goodman</name>
<affiliation wicri:level="4"><nlm:aff id="A6">Cornell University, College of Veterinary Medicine, Department of Population Medicine and Diagnostic Sciences, Ithaca, NY, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Cornell University, College of Veterinary Medicine, Department of Population Medicine and Diagnostic Sciences, Ithaca, NY</wicri:regionArea>
<orgName type="university">Université Cornell</orgName>
<placeName><settlement type="city">Ithaca (New York)</settlement>
<region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bodenreider, Christophe" sort="Bodenreider, Christophe" uniqKey="Bodenreider C" first="Christophe" last="Bodenreider">Christophe Bodenreider</name>
<affiliation><nlm:aff id="A1">Novartis Institute for Tropical Diseases, Singapore 138670</nlm:aff>
<wicri:noCountry code="subfield">Singapore 138670</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Feng, Gu" sort="Feng, Gu" uniqKey="Feng G" first="Gu" last="Feng">Gu Feng</name>
<affiliation><nlm:aff id="A1">Novartis Institute for Tropical Diseases, Singapore 138670</nlm:aff>
<wicri:noCountry code="subfield">Singapore 138670</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Zhang, Lijun" sort="Zhang, Lijun" uniqKey="Zhang L" first="Lijun" last="Zhang">Lijun Zhang</name>
<affiliation wicri:level="1"><nlm:aff id="A7">China Novartis Institute for Biomedical Research, Shanghai 201203, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>China Novartis Institute for Biomedical Research, Shanghai 201203</wicri:regionArea>
<wicri:noRegion>Shanghai 201203</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Blasco, Francesca" sort="Blasco, Francesca" uniqKey="Blasco F" first="Francesca" last="Blasco">Francesca Blasco</name>
<affiliation><nlm:aff id="A1">Novartis Institute for Tropical Diseases, Singapore 138670</nlm:aff>
<wicri:noCountry code="subfield">Singapore 138670</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Wagner, Juergen" sort="Wagner, Juergen" uniqKey="Wagner J" first="Juergen" last="Wagner">Juergen Wagner</name>
<affiliation><nlm:aff id="A1">Novartis Institute for Tropical Diseases, Singapore 138670</nlm:aff>
<wicri:noCountry code="subfield">Singapore 138670</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Leong, F Joel" sort="Leong, F Joel" uniqKey="Leong F" first="F. Joel" last="Leong">F. Joel Leong</name>
<affiliation><nlm:aff id="A1">Novartis Institute for Tropical Diseases, Singapore 138670</nlm:aff>
<wicri:noCountry code="subfield">Singapore 138670</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Striepen, Boris" sort="Striepen, Boris" uniqKey="Striepen B" first="Boris" last="Striepen">Boris Striepen</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA</wicri:regionArea>
<wicri:noRegion>GA</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A4">Department of Cellular Biology, University of Georgia, Athens, GA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Cellular Biology, University of Georgia, Athens, GA</wicri:regionArea>
<wicri:noRegion>GA</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Diagana, Thierry T" sort="Diagana, Thierry T" uniqKey="Diagana T" first="Thierry T." last="Diagana">Thierry T. Diagana</name>
<affiliation><nlm:aff id="A1">Novartis Institute for Tropical Diseases, Singapore 138670</nlm:aff>
<wicri:noCountry code="subfield">Singapore 138670</wicri:noCountry>
</affiliation>
</author>
</analytic>
<series><title level="j">Nature</title>
<idno type="ISSN">0028-0836</idno>
<idno type="eISSN">1476-4687</idno>
<imprint><date when="2017">2017</date>
</imprint>
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<front><div type="abstract" xml:lang="en"><p id="P1">Diarrheal disease is responsible for 8.6% of global child mortality. Recent epidemiological studies found the protozoan parasite <italic>Cryptosporidium</italic>
 to be a leading cause of pediatric diarrhea with particularly grave impact on infants and immunocompromised individuals. There is neither a vaccine nor effective treatment. We establish a drug discovery process built on scalable phenotypic assays and mouse models that takes advantage of transgenic parasites. Screening a library of compounds with anti-parasitic activity we identified pyrazolopyridines as inhibitors of <italic>Cryptosporidium parvum</italic>
 and <italic>C. hominis</italic>
. Oral treatment with the pyrazolopyridine KDU731 results in potent reduction in intestinal infection of immunocompromised mice. Treatment also leads to rapid resolution of diarrhea and dehydration in neonatal calves, a clinical model of cryptosporidiosis that closely resembles human infection. Our results suggest the <italic>Cryptosporidium</italic>
 lipid kinase PI(4)K as a target for pyrazolopyridines and warrant further preclinical evaluation of KDU731 as a drug candidate for the treatment of cryptosporidiosis.</p>
</div>
</front>
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</author>
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<affiliations><list><country><li>République populaire de Chine</li>
<li>États-Unis</li>
</country>
<region><li>État de New York</li>
</region>
<settlement><li>Ithaca (New York)</li>
</settlement>
<orgName><li>Université Cornell</li>
</orgName>
</list>
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<name sortKey="Bonamy, Ghislain M C" sort="Bonamy, Ghislain M C" uniqKey="Bonamy G" first="Ghislain M. C." last="Bonamy">Ghislain M. C. Bonamy</name>
<name sortKey="Chao, Alexander T" sort="Chao, Alexander T" uniqKey="Chao A" first="Alexander T." last="Chao">Alexander T. Chao</name>
<name sortKey="Diagana, Thierry T" sort="Diagana, Thierry T" uniqKey="Diagana T" first="Thierry T." last="Diagana">Thierry T. Diagana</name>
<name sortKey="Feng, Gu" sort="Feng, Gu" uniqKey="Feng G" first="Gu" last="Feng">Gu Feng</name>
<name sortKey="Gedeck, Peter" sort="Gedeck, Peter" uniqKey="Gedeck P" first="Peter" last="Gedeck">Peter Gedeck</name>
<name sortKey="Kondreddi, Ravinder R" sort="Kondreddi, Ravinder R" uniqKey="Kondreddi R" first="Ravinder R." last="Kondreddi">Ravinder R. Kondreddi</name>
<name sortKey="Lakshminarayana, Suresh B" sort="Lakshminarayana, Suresh B" uniqKey="Lakshminarayana S" first="Suresh B." last="Lakshminarayana">Suresh B. Lakshminarayana</name>
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<name sortKey="Wagner, Juergen" sort="Wagner, Juergen" uniqKey="Wagner J" first="Juergen" last="Wagner">Juergen Wagner</name>
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<name sortKey="Herbert, Gillian T" sort="Herbert, Gillian T" uniqKey="Herbert G" first="Gillian T." last="Herbert">Gillian T. Herbert</name>
<name sortKey="Noh, Susan" sort="Noh, Susan" uniqKey="Noh S" first="Susan" last="Noh">Susan Noh</name>
<name sortKey="Noh, Susan" sort="Noh, Susan" uniqKey="Noh S" first="Susan" last="Noh">Susan Noh</name>
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<name sortKey="Sy, Tracy" sort="Sy, Tracy" uniqKey="Sy T" first="Tracy" last="Sy">Tracy Sy</name>
<name sortKey="Tandel, Jayesh" sort="Tandel, Jayesh" uniqKey="Tandel J" first="Jayesh" last="Tandel">Jayesh Tandel</name>
<name sortKey="Zambriski, Jennifer A" sort="Zambriski, Jennifer A" uniqKey="Zambriski J" first="Jennifer A." last="Zambriski">Jennifer A. Zambriski</name>
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A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis

A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis

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