A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis
Identifieur interne : 000F35 ( Main/Curation ); précédent : 000F34; suivant : 000F36A 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. DiaganaSource :
- Nature [ 0028-0836 ] ; 2017.
Abstract
Diarrheal disease is responsible for 8.6% of global child mortality. Recent epidemiological studies found the protozoan parasite
Url:
DOI: 10.1038/nature22337
PubMed: 28562588
PubMed Central: 5473467
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Le document en format XML
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PI(4)K inhibitor is a drug candidate for cryptosporidiosis</title>
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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>
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<affiliation wicri:level="2"><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>
<placeName><region type="state">Géorgie (États-Unis)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Sateriale, Adam" sort="Sateriale, Adam" uniqKey="Sateriale A" first="Adam" last="Sateriale">Adam Sateriale</name>
<affiliation wicri:level="2"><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>
<placeName><region type="state">Géorgie (États-Unis)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Tandel, Jayesh" sort="Tandel, Jayesh" uniqKey="Tandel J" first="Jayesh" last="Tandel">Jayesh Tandel</name>
<affiliation wicri:level="2"><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>
<placeName><region type="state">Géorgie (États-Unis)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Noh, Susan" sort="Noh, Susan" uniqKey="Noh S" first="Susan" last="Noh">Susan Noh</name>
<affiliation wicri:level="2"><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>
<placeName><region type="state">Washington (État)</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><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>
<placeName><region type="state">Washington (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lakshminarayana, Suresh B" sort="Lakshminarayana, Suresh B" uniqKey="Lakshminarayana S" first="Suresh B." last="Lakshminarayana">Suresh B. Lakshminarayana</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="Lim, Siau H" sort="Lim, Siau H" uniqKey="Lim S" first="Siau H." last="Lim">Siau H. Lim</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="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>
<placeName><region type="state">État de New York</region>
<settlement type="city">Ithaca (New York)</settlement>
</placeName>
<orgName type="university">Université Cornell</orgName>
</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="2"><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>
<placeName><region type="state">Géorgie (États-Unis)</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><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>
<placeName><region type="state">Géorgie (États-Unis)</region>
</placeName>
</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>
</series>
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<profileDesc><textClass></textClass>
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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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