A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis
Identifieur interne : 000708 ( Ncbi/Merge ); précédent : 000707; suivant : 000709A 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
Links toward previous steps (curation, corpus...)
- to stream Pmc, to step Corpus: 000A55
- to stream Pmc, to step Curation: 000A55
- to stream Pmc, to step Checkpoint: 000439
Links to Exploration step
PMC:5473467Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">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>
<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="Vinayak, Sumiti" sort="Vinayak, Sumiti" uniqKey="Vinayak S" first="Sumiti" last="Vinayak">Sumiti Vinayak</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="Zambriski, Jennifer A" sort="Zambriski, Jennifer A" uniqKey="Zambriski J" first="Jennifer A." last="Zambriski">Jennifer A. Zambriski</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>
</author>
<author><name sortKey="Chao, Alexander T" sort="Chao, Alexander T" uniqKey="Chao A" first="Alexander T." last="Chao">Alexander T. Chao</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="Sy, Tracy" sort="Sy, Tracy" uniqKey="Sy T" first="Tracy" last="Sy">Tracy Sy</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>
</author>
<author><name sortKey="Noble, Christian G" sort="Noble, Christian G" uniqKey="Noble C" first="Christian G." last="Noble">Christian G. Noble</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="Bonamy, Ghislain M C" sort="Bonamy, Ghislain M C" uniqKey="Bonamy G" first="Ghislain M. C." last="Bonamy">Ghislain M. C. Bonamy</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="Kondreddi, Ravinder R" sort="Kondreddi, Ravinder R" uniqKey="Kondreddi R" first="Ravinder R." last="Kondreddi">Ravinder R. Kondreddi</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="Zou, Bin" sort="Zou, Bin" uniqKey="Zou B" first="Bin" last="Zou">Bin Zou</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="Gedeck, Peter" sort="Gedeck, Peter" uniqKey="Gedeck P" first="Peter" last="Gedeck">Peter Gedeck</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="Brooks, Carrie F" sort="Brooks, Carrie F" uniqKey="Brooks C" first="Carrie F." last="Brooks">Carrie F. Brooks</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="Herbert, Gillian T" sort="Herbert, Gillian T" uniqKey="Herbert G" first="Gillian T." last="Herbert">Gillian T. Herbert</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="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>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">28562588</idno>
<idno type="pmc">5473467</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473467</idno>
<idno type="RBID">PMC:5473467</idno>
<idno type="doi">10.1038/nature22337</idno>
<date when="2017">2017</date>
<idno type="wicri:Area/Pmc/Corpus">000A55</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A55</idno>
<idno type="wicri:Area/Pmc/Curation">000A55</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000A55</idno>
<idno type="wicri:Area/Pmc/Checkpoint">000439</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000439</idno>
<idno type="wicri:Area/Ncbi/Merge">000708</idno>
</publicationStmt>
<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>
<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="Vinayak, Sumiti" sort="Vinayak, Sumiti" uniqKey="Vinayak S" first="Sumiti" last="Vinayak">Sumiti Vinayak</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="Zambriski, Jennifer A" sort="Zambriski, Jennifer A" uniqKey="Zambriski J" first="Jennifer A." last="Zambriski">Jennifer A. Zambriski</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>
</author>
<author><name sortKey="Chao, Alexander T" sort="Chao, Alexander T" uniqKey="Chao A" first="Alexander T." last="Chao">Alexander T. Chao</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="Sy, Tracy" sort="Sy, Tracy" uniqKey="Sy T" first="Tracy" last="Sy">Tracy Sy</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>
</author>
<author><name sortKey="Noble, Christian G" sort="Noble, Christian G" uniqKey="Noble C" first="Christian G." last="Noble">Christian G. Noble</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="Bonamy, Ghislain M C" sort="Bonamy, Ghislain M C" uniqKey="Bonamy G" first="Ghislain M. C." last="Bonamy">Ghislain M. C. Bonamy</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="Kondreddi, Ravinder R" sort="Kondreddi, Ravinder R" uniqKey="Kondreddi R" first="Ravinder R." last="Kondreddi">Ravinder R. Kondreddi</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="Zou, Bin" sort="Zou, Bin" uniqKey="Zou B" first="Bin" last="Zou">Bin Zou</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="Gedeck, Peter" sort="Gedeck, Peter" uniqKey="Gedeck P" first="Peter" last="Gedeck">Peter Gedeck</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="Brooks, Carrie F" sort="Brooks, Carrie F" uniqKey="Brooks C" first="Carrie F." last="Brooks">Carrie F. Brooks</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="Herbert, Gillian T" sort="Herbert, Gillian T" uniqKey="Herbert G" first="Gillian T." last="Herbert">Gillian T. Herbert</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="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>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<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>
<back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Liu, L" uniqKey="Liu L">L Liu</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kotloff, Kl" uniqKey="Kotloff K">KL Kotloff</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Platts Mills, Ja" uniqKey="Platts Mills J">JA Platts-Mills</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Checkley, W" uniqKey="Checkley W">W Checkley</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Amadi, B" uniqKey="Amadi B">B Amadi</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Amadi, B" uniqKey="Amadi B">B Amadi</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Striepen, B" uniqKey="Striepen B">B Striepen</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Vinayak, S" uniqKey="Vinayak S">S Vinayak</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Rottmann, M" uniqKey="Rottmann M">M Rottmann</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Burstner, N" uniqKey="Burstner N">N Burstner</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Meister, S" uniqKey="Meister S">S Meister</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mcnamara, Cw" uniqKey="Mcnamara C">CW McNamara</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Zou, B" uniqKey="Zou B">B Zou</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Chatterjee, Ak" uniqKey="Chatterjee A">AK Chatterjee</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Xiao, L" uniqKey="Xiao L">L Xiao</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Zeeman, Am" uniqKey="Zeeman A">AM Zeeman</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ghidelli Disse, S" uniqKey="Ghidelli Disse S">S Ghidelli-Disse</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Huston, Cd" uniqKey="Huston C">CD Huston</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Manjunatha, Uh" uniqKey="Manjunatha U">UH Manjunatha</name>
</author>
<author><name sortKey="Chao, At" uniqKey="Chao A">AT Chao</name>
</author>
<author><name sortKey="Leong, Fj" uniqKey="Leong F">FJ Leong</name>
</author>
<author><name sortKey="Diagana, Tt" uniqKey="Diagana T">TT Diagana</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Branchini, Br" uniqKey="Branchini B">BR Branchini</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Theodos, Cm" uniqKey="Theodos C">CM Theodos</name>
</author>
<author><name sortKey="Griffiths, Jk" uniqKey="Griffiths J">JK Griffiths</name>
</author>
<author><name sortKey="D Onfro, J" uniqKey="D Onfro J">J D'Onfro</name>
</author>
<author><name sortKey="Fairfield, A" uniqKey="Fairfield A">A Fairfield</name>
</author>
<author><name sortKey="Tzipori, S" uniqKey="Tzipori S">S Tzipori</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Zambriski, Ja" uniqKey="Zambriski J">JA Zambriski</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Zambriski, Ja" uniqKey="Zambriski J">JA Zambriski</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bellosa, Ml" uniqKey="Bellosa M">ML Bellosa</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Younis, Y" uniqKey="Younis Y">Y Younis</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Castellanos Gonzalez, A" uniqKey="Castellanos Gonzalez A">A Castellanos-Gonzalez</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bessoff, K" uniqKey="Bessoff K">K Bessoff</name>
</author>
<author><name sortKey="Sateriale, A" uniqKey="Sateriale A">A Sateriale</name>
</author>
<author><name sortKey="Lee, Kk" uniqKey="Lee K">KK Lee</name>
</author>
<author><name sortKey="Huston, Cd" uniqKey="Huston C">CD Huston</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Sharling, L" uniqKey="Sharling L">L Sharling</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Chao, At" uniqKey="Chao A">AT Chao</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Manjunatha, Uh" uniqKey="Manjunatha U">UH Manjunatha</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Faller, B" uniqKey="Faller B">B Faller</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Faller, B" uniqKey="Faller B">B Faller</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ames, Bn" uniqKey="Ames B">BN Ames</name>
</author>
<author><name sortKey="Lee, Fd" uniqKey="Lee F">FD Lee</name>
</author>
<author><name sortKey="Durston, We" uniqKey="Durston W">WE Durston</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Jothikumar, N" uniqKey="Jothikumar N">N Jothikumar</name>
</author>
<author><name sortKey="Da Silva, Aj" uniqKey="Da Silva A">AJ da Silva</name>
</author>
<author><name sortKey="Moura, I" uniqKey="Moura I">I Moura</name>
</author>
<author><name sortKey="Qvarnstrom, Y" uniqKey="Qvarnstrom Y">Y Qvarnstrom</name>
</author>
<author><name sortKey="Hill, Vr" uniqKey="Hill V">VR Hill</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Dreier, J" uniqKey="Dreier J">J Dreier</name>
</author>
<author><name sortKey="Stormer, M" uniqKey="Stormer M">M Stormer</name>
</author>
<author><name sortKey="Kleesiek, K" uniqKey="Kleesiek K">K Kleesiek</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Operario, Dj" uniqKey="Operario D">DJ Operario</name>
</author>
<author><name sortKey="Bristol, Ls" uniqKey="Bristol L">LS Bristol</name>
</author>
<author><name sortKey="Liotta, J" uniqKey="Liotta J">J Liotta</name>
</author>
<author><name sortKey="Nydam, Dv" uniqKey="Nydam D">DV Nydam</name>
</author>
<author><name sortKey="Houpt, Er" uniqKey="Houpt E">ER Houpt</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Diagana, Tt" uniqKey="Diagana T">TT Diagana</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Hoepfner, D" uniqKey="Hoepfner D">D Hoepfner</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Abrahamsen, Ms" uniqKey="Abrahamsen M">MS Abrahamsen</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Xu, P" uniqKey="Xu P">P Xu</name>
</author>
</analytic>
</biblStruct>
</listBibl>
</div1>
</back>
</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">0410462</journal-id>
<journal-id journal-id-type="pubmed-jr-id">6011</journal-id>
<journal-id journal-id-type="nlm-ta">Nature</journal-id>
<journal-id journal-id-type="iso-abbrev">Nature</journal-id>
<journal-title-group><journal-title>Nature</journal-title>
</journal-title-group>
<issn pub-type="ppub">0028-0836</issn>
<issn pub-type="epub">1476-4687</issn>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">28562588</article-id>
<article-id pub-id-type="pmc">5473467</article-id>
<article-id pub-id-type="doi">10.1038/nature22337</article-id>
<article-id pub-id-type="manuscript">EMS72141</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>A <italic>Cryptosporidium</italic>
PI(4)K inhibitor is a drug candidate for cryptosporidiosis</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Manjunatha</surname>
<given-names>Ujjini H.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Vinayak</surname>
<given-names>Sumiti</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Zambriski</surname>
<given-names>Jennifer A.</given-names>
</name>
<xref ref-type="aff" rid="A3">3</xref>
<xref ref-type="corresp" rid="CR1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chao</surname>
<given-names>Alexander T.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sy</surname>
<given-names>Tracy</given-names>
</name>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Noble</surname>
<given-names>Christian G.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bonamy</surname>
<given-names>Ghislain M.C.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kondreddi</surname>
<given-names>Ravinder R.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zou</surname>
<given-names>Bin</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gedeck</surname>
<given-names>Peter</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Brooks</surname>
<given-names>Carrie F.</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Herbert</surname>
<given-names>Gillian T.</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sateriale</surname>
<given-names>Adam</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tandel</surname>
<given-names>Jayesh</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Noh</surname>
<given-names>Susan</given-names>
</name>
<xref ref-type="aff" rid="A3">3</xref>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lakshminarayana</surname>
<given-names>Suresh B.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lim</surname>
<given-names>Siau H.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Goodman</surname>
<given-names>Laura B.</given-names>
</name>
<xref ref-type="aff" rid="A6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bodenreider</surname>
<given-names>Christophe</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Feng</surname>
<given-names>Gu</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhang</surname>
<given-names>Lijun</given-names>
</name>
<xref ref-type="aff" rid="A7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Blasco</surname>
<given-names>Francesca</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wagner</surname>
<given-names>Juergen</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Leong</surname>
<given-names>F. Joel</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Striepen</surname>
<given-names>Boris</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A4">4</xref>
<xref ref-type="corresp" rid="CR1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Diagana</surname>
<given-names>Thierry T.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="corresp" rid="CR1">*</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Novartis Institute for Tropical Diseases, Singapore 138670</aff>
<aff id="A2"><label>2</label>
Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA</aff>
<aff id="A3"><label>3</label>
Washington State University, College of Veterinary Medicine, Paul G. Allen School for Global Animal Health, Pullman, WA, USA</aff>
<aff id="A4"><label>4</label>
Department of Cellular Biology, University of Georgia, Athens, GA, USA</aff>
<aff id="A5"><label>5</label>
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</aff>
<aff id="A6"><label>6</label>
Cornell University, College of Veterinary Medicine, Department of Population Medicine and Diagnostic Sciences, Ithaca, NY, USA</aff>
<aff id="A7"><label>7</label>
China Novartis Institute for Biomedical Research, Shanghai 201203, China</aff>
<author-notes><corresp id="CR1"><label>*</label>
Correspondence and requests for materials should be addressed to<email>striepen@uga.edu</email>
; <email>jzambriski@vetmed.wsu.edu</email>
; <email>thierry.diagana@novartis.com</email>
.</corresp>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>5</day>
<month>6</month>
<year>2017</year>
</pub-date>
<pub-date pub-type="epub"><day>31</day>
<month>5</month>
<year>2017</year>
</pub-date>
<pub-date pub-type="ppub"><day>15</day>
<month>6</month>
<year>2017</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>30</day>
<month>11</month>
<year>2017</year>
</pub-date>
<volume>546</volume>
<issue>7658</issue>
<fpage>376</fpage>
<lpage>380</lpage>
<pmc-comment>elocation-id from pubmed: 10.1038/nature22337</pmc-comment>
<permissions><license><license-p>Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:<ext-link ext-link-type="uri" xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms">http://www.nature.com/authors/editorial_policies/license.html#terms</ext-link>
</license-p>
</license>
</permissions>
<abstract><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>
</abstract>
</article-meta>
</front>
<floats-group><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label>
<caption><title>Pyrazolopyridine analogs exhibit potent anti-<italic>Cryptosporidium</italic>
activity.</title>
<p><bold>a</bold>
, <italic>C. parvum</italic>
phenotypic screening against a focused library of 6,220 compounds (% inhibition at 5 μM). Hits with inhibition >3 SD are shown in red <bold>b</bold>
, Structure of the pyrazolopyridine lead KU731. <bold>c</bold>
, <italic>In vitro</italic>
activity of KDU731 (red), MMV3900048 (maroon) and nitazoxanide (black) against <italic>C. parvum</italic>
(solid line) and <italic>C. hominis</italic>
(dashed line). <bold>d</bold>
, Correlation of growth inhibition (EC<sub>50</sub>
) of selected compounds between <italic>C. parvum</italic>
(Cp) and <italic>P. falciparum</italic>
(Pf). Pyrazolopyridine analogs are shown in red, imidazopyrazines in blue, quinoxaline in green, and diaryl-aminopyridine in maroon. <bold>e</bold>
, Correlation of growth inhibition (EC<sub>50</sub>
) between <italic>C. parvum</italic>
and <italic>C. hominis</italic>
for selected compounds. <bold>f</bold>
, Inhibition of phosphatidylinositide kinase activity of purified enzyme by KDU731, KDU691, MMV390048 and BQR695 (means ± s.e. with at least 3 biological replicates) in presence of 3 μM ATP. <bold>g</bold>
, Correlation between inhibition of PI kinase activity of purified CpPI(4)K enzyme (IC<sub>50</sub>
) and growth inhibition (EC<sub>50</sub>
) of <italic>C. parvum</italic>
with selected compounds (colors as in <bold>d</bold>
). <bold>h,</bold>
CpPI(4)K activity across a range of ATP concentrations in the presence of 1.56 - 50 nM KDU731. Data shown in <bold>c</bold>
and <bold>f</bold>
represent mean ± s.e., n=3 biological replicates, representative data shown. Experiments shown in <bold>d</bold>
, <bold>e</bold>
, and <bold>g</bold>
were repeated at least twice and geometric mean EC<sub>50</sub>
values are plotted, and <bold>h</bold>
has been repeated twice (biological replicates) and one representative assay is shown.</p>
</caption>
<graphic xlink:href="emss-72141-f001"></graphic>
</fig>
<fig id="F2" orientation="portrait" position="float"><label>Figure 2</label>
<caption><title>KDU731 has potent activity against <italic>Cryptosporidium</italic>
in immunocompromised IFN-γ KO mice.</title>
<p><bold>a</bold>
, Mice were infected with 10,000 <italic>C. parvum</italic>
UGA1 Nluc or UGA2 Fluc oocysts. Parasite load in the feces was determined by measuring fecal Nluc activity and parasite tissue load was quantified by whole animal imaging of Fluc activity. Different 7 day treatment courses are indicated in red. Fecal luciferase measurements of individual mice with treatment initiated after 3 (<bold>b</bold>
) or 11 (<bold>c</bold>
) days of infection (red, vehicle control shown in black), n=5 and n=9 mice respectively, representative of two biological replicates for b and c. <bold>d</bold>
, Histology of the ileum of infected mice (shown in <bold>c</bold>
) after one week of KDU731 treatment compared to vehicle treated control on day 18 (n=3 biological replicates, representative images shown here). Note numerous intracellular parasite stages (white arrowheads) and extracellular oocysts (black arrowhead) in the control absent in the treated mice. Vehicle treated animals showed disorganized columnar epithelial cells and loss of brush border when compared to KDU731 treated mice. White box indicates section shown at higher magnification to the right. Mice (n=5) infected with UGA2 FLuc were treated on day 7 with 10mg/kg of KDU731 (red (<bold>e</bold>
) and <bold>g</bold>
), 100 mg/kg nitazoxanide (red (<bold>f</bold>
), also see <xref ref-type="fig" rid="F8">Extended Data Fig. 5</xref>
), or vehicle (black, <bold>e</bold>
and <bold>f</bold>
) for one week. Animals were monitored by whole-animal-imaging and a radiance scale and quantification of total flux in photon/sec is shown. *Animals shown on the baseline were below the level of detection.</p>
</caption>
<graphic xlink:href="emss-72141-f002"></graphic>
</fig>
<fig id="F3" orientation="portrait" position="float"><label>Figure 3</label>
<caption><title>Therapeutic efficacy of KDU731 in neonatal calf clinical model of cryptosporidiosis.</title>
<p><bold>a</bold>
, Within 48 h of birth, calves were challenged with 5x10<sup>7</sup>
<italic>C. parvum</italic>
oocysts. Fecal oocyst shedding was enumerated via qPCR and calves were clinically evaluated every 12 h. Oral treatment with KDU731 (5mg/kg every 12 hours for 7 days) was initiated when calves showed severe diarrhea (Fecal Consistency Score = 3) and oocysts in their feces. KDU731 treated calves shed significantly fewer oocysts in their stool (<bold>b</bold>
), had significantly fewer days of severe diarrhea (<bold>c</bold>
) and were significantly less dehydrated (<bold>d</bold>
) than untreated calves. <bold>e</bold>
, Day 1 and day 7 plasma PK profile of KDU731. Data shown here (panels b,c,d, e) are from infected calves that were treated with vehicle (n=6) or KDU731 (n = 7), n represents the number of calves. <italic>In vitro</italic>
EC<sub>90</sub>
is shown as dotted line. Error bars are SEM. Data shown here (c and d) as a “box and whiskers” plot, the box extends from the 25th to 75th percentiles and whiskers with min to max showing all data points. Data in panel b and e were determined to display non-Gaussian distribution and were log-transformed prior to statistical analysis using <italic>t</italic>
-tests with two-tailed *<italic>P</italic>
<0.05, **0.01, ***0.001, and ****0.0001. Panels c and d were determined to be normally distributed and analyzed using t-tests<italic>.</italic>
</p>
</caption>
<graphic xlink:href="emss-72141-f003"></graphic>
</fig>
<table-wrap id="T1" position="float" orientation="portrait"><label>Table 1</label>
<caption><title>Activity of pyrazolopyridine analogs and other known PI(4) kinase inhibitors</title>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Compound</th>
<th align="left" rowspan="1" colspan="1"><italic>Cp</italic>
CPE EC<sub>50</sub>
</th>
<th align="left" rowspan="1" colspan="1"><italic>Cp</italic>
HCI IC<sub>50</sub>
</th>
<th align="left" rowspan="1" colspan="1"><italic>Ch</italic>
CPE EC<sub>50</sub>
</th>
<th align="left" rowspan="1" colspan="1"><italic>Cp</italic>
PI(4)K IC<sub>50</sub>
</th>
<th align="left" rowspan="1" colspan="1"><italic>Pf</italic>
3D7 IC<sub>50</sub>
</th>
<th align="left" rowspan="1" colspan="1">HepG2 CC<sub>50</sub>
</th>
</tr>
</thead>
<tbody><tr><td align="left" rowspan="1" colspan="1">KDU731</td>
<td align="left" rowspan="1" colspan="1">0.107 ± 0.039</td>
<td align="left" rowspan="1" colspan="1">0.063 ± 0.028</td>
<td align="left" rowspan="1" colspan="1">0.130 ± 0.074</td>
<td align="left" rowspan="1" colspan="1">0.025 ± 0.004</td>
<td align="left" rowspan="1" colspan="1">0.003 ± 0.001</td>
<td align="left" rowspan="1" colspan="1">15.621 ± 8.621</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">KDU691</td>
<td align="left" rowspan="1" colspan="1">0.096 ± 0.044</td>
<td align="left" rowspan="1" colspan="1">0.054 ± 0.029</td>
<td align="left" rowspan="1" colspan="1">0.082 ± 0.017</td>
<td align="left" rowspan="1" colspan="1">0.017 ± 0.012</td>
<td align="left" rowspan="1" colspan="1">0.108 ± 0.061</td>
<td align="left" rowspan="1" colspan="1">27.291 ± 14.169</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">MMV390048</td>
<td align="left" rowspan="1" colspan="1">12.792 ± 6.264</td>
<td align="left" rowspan="1" colspan="1">13.422</td>
<td align="left" rowspan="1" colspan="1">11.85 ± 2.758</td>
<td align="left" rowspan="1" colspan="1">8.335 ± 2.355</td>
<td align="left" rowspan="1" colspan="1">0.042 ± 0.022</td>
<td align="left" rowspan="1" colspan="1">26.156 ± 16.063</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">BQR695</td>
<td align="left" rowspan="1" colspan="1">11.837 ± 1.889</td>
<td align="left" rowspan="1" colspan="1">8.344</td>
<td align="left" rowspan="1" colspan="1">8.565</td>
<td align="left" rowspan="1" colspan="1">7.305 ± 0.841</td>
<td align="left" rowspan="1" colspan="1">0.118 ± 0.055</td>
<td align="left" rowspan="1" colspan="1">26.711 ± 13.870</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Nitazoxanide</td>
<td align="left" rowspan="1" colspan="1">14.286 ± 7.127</td>
<td align="left" rowspan="1" colspan="1">2.927 ± 0.808</td>
<td align="left" rowspan="1" colspan="1">> 20.000</td>
<td align="left" rowspan="1" colspan="1">> 10.000</td>
<td align="left" rowspan="1" colspan="1">> 10.000</td>
<td align="left" rowspan="1" colspan="1">12.749 ± 2.378</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">KDU370</td>
<td align="left" rowspan="1" colspan="1">1.540</td>
<td align="left" rowspan="1" colspan="1">nd</td>
<td align="left" rowspan="1" colspan="1">2.543</td>
<td align="left" rowspan="1" colspan="1">0.212</td>
<td align="left" rowspan="1" colspan="1">0.074 ± 0.032</td>
<td align="left" rowspan="1" colspan="1">> 50.000</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">KDZ464</td>
<td align="left" rowspan="1" colspan="1">0.113 ± 0.072</td>
<td align="left" rowspan="1" colspan="1">0.232</td>
<td align="left" rowspan="1" colspan="1">0.119</td>
<td align="left" rowspan="1" colspan="1">0.003</td>
<td align="left" rowspan="1" colspan="1">0.005 ± 0.001</td>
<td align="left" rowspan="1" colspan="1">21.222 ± 10.594</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">LNN134</td>
<td align="left" rowspan="1" colspan="1">1.951 ± 0.340</td>
<td align="left" rowspan="1" colspan="1">1.031</td>
<td align="left" rowspan="1" colspan="1">1.937</td>
<td align="left" rowspan="1" colspan="1">0.488</td>
<td align="left" rowspan="1" colspan="1">0.126 ± 0.115</td>
<td align="left" rowspan="1" colspan="1">40.025 ± 17.278</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">LMW740</td>
<td align="left" rowspan="1" colspan="1">> 20.000</td>
<td align="left" rowspan="1" colspan="1">> 20.000</td>
<td align="left" rowspan="1" colspan="1">> 20.000</td>
<td align="left" rowspan="1" colspan="1">>10</td>
<td align="left" rowspan="1" colspan="1">0.521</td>
<td align="left" rowspan="1" colspan="1">> 50.000</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">KEL204</td>
<td align="left" rowspan="1" colspan="1">> 20.000</td>
<td align="left" rowspan="1" colspan="1">> 20.000</td>
<td align="left" rowspan="1" colspan="1">> 20.000</td>
<td align="left" rowspan="1" colspan="1">3.701</td>
<td align="left" rowspan="1" colspan="1">1.432</td>
<td align="left" rowspan="1" colspan="1">> 50.000</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="TFN1"><p id="P61"><italic>Cp</italic>
, <italic>C. parvum</italic>
; <italic>Ch</italic>
, <italic>C. hominis</italic>
; <italic>Pf</italic>
, <italic>P. falciparum</italic>
; CPE, Cytopathic Effect assay; HCI; High Content Imaging assay</p>
</fn>
<fn id="TFN2"><p id="P62">EC<sub>50</sub>
, IC<sub>50</sub>
and CC<sub>50</sub>
<italic>values</italic>
are in μM nd, not determined</p>
</fn>
<fn id="TFN3"><p id="P63">Data shown here are means ± s.e. , n=3 biological replicates</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
<affiliations><list><country><li>République populaire de Chine</li>
<li>États-Unis</li>
</country>
<region><li>Géorgie (États-Unis)</li>
<li>Washington (État)</li>
<li>État de New York</li>
</region>
<settlement><li>Ithaca (New York)</li>
</settlement>
<orgName><li>Université Cornell</li>
</orgName>
</list>
<tree><noCountry><name sortKey="Blasco, Francesca" sort="Blasco, Francesca" uniqKey="Blasco F" first="Francesca" last="Blasco">Francesca Blasco</name>
<name sortKey="Bodenreider, Christophe" sort="Bodenreider, Christophe" uniqKey="Bodenreider C" first="Christophe" last="Bodenreider">Christophe Bodenreider</name>
<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>
<name sortKey="Leong, F Joel" sort="Leong, F Joel" uniqKey="Leong F" first="F. Joel" last="Leong">F. Joel Leong</name>
<name sortKey="Lim, Siau H" sort="Lim, Siau H" uniqKey="Lim S" first="Siau H." last="Lim">Siau H. Lim</name>
<name sortKey="Manjunatha, Ujjini H" sort="Manjunatha, Ujjini H" uniqKey="Manjunatha U" first="Ujjini H." last="Manjunatha">Ujjini H. Manjunatha</name>
<name sortKey="Noble, Christian G" sort="Noble, Christian G" uniqKey="Noble C" first="Christian G." last="Noble">Christian G. Noble</name>
<name sortKey="Wagner, Juergen" sort="Wagner, Juergen" uniqKey="Wagner J" first="Juergen" last="Wagner">Juergen Wagner</name>
<name sortKey="Zou, Bin" sort="Zou, Bin" uniqKey="Zou B" first="Bin" last="Zou">Bin Zou</name>
</noCountry>
<country name="États-Unis"><region name="Géorgie (États-Unis)"><name sortKey="Vinayak, Sumiti" sort="Vinayak, Sumiti" uniqKey="Vinayak S" first="Sumiti" last="Vinayak">Sumiti Vinayak</name>
</region>
<name sortKey="Brooks, Carrie F" sort="Brooks, Carrie F" uniqKey="Brooks C" first="Carrie F." last="Brooks">Carrie F. Brooks</name>
<name sortKey="Goodman, Laura B" sort="Goodman, Laura B" uniqKey="Goodman L" first="Laura B." last="Goodman">Laura B. Goodman</name>
<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>
<name sortKey="Sateriale, Adam" sort="Sateriale, Adam" uniqKey="Sateriale A" first="Adam" last="Sateriale">Adam Sateriale</name>
<name sortKey="Striepen, Boris" sort="Striepen, Boris" uniqKey="Striepen B" first="Boris" last="Striepen">Boris Striepen</name>
<name sortKey="Striepen, Boris" sort="Striepen, Boris" uniqKey="Striepen B" first="Boris" last="Striepen">Boris Striepen</name>
<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>
</country>
<country name="République populaire de Chine"><noRegion><name sortKey="Zhang, Lijun" sort="Zhang, Lijun" uniqKey="Zhang L" first="Lijun" last="Zhang">Lijun Zhang</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/CovidV2/Data/Ncbi/Merge
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000708 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Ncbi/Merge/biblio.hfd -nk 000708 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Wicri/Sante |area= CovidV2 |flux= Ncbi |étape= Merge |type= RBID |clé= PMC:5473467 |texte= A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Ncbi/Merge/RBID.i -Sk "pubmed:28562588" \ | HfdSelect -Kh $EXPLOR_AREA/Data/Ncbi/Merge/biblio.hfd \ | NlmPubMed2Wicri -a CovidV2
![]() | This area was generated with Dilib version V0.6.33. | ![]() |