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dc.contributor.authorVaidya, Akhil B
dc.contributor.authorMorrisey, Joanne M
dc.contributor.authorZhang, Zhongsheng
dc.contributor.authorDas, Sudipta
dc.contributor.authorDaly, Thomas M
dc.contributor.authorOtto, Thomas D
dc.contributor.authorSpillman, Natalie J
dc.contributor.authorWyvratt, Matthew
dc.contributor.authorSiegl, Peter
dc.contributor.authorMarfurt, Jutta
dc.contributor.authorWirjanata, Grennady
dc.contributor.authorSebayang, Boni F
dc.contributor.authorPrice, Ric N
dc.contributor.authorChatterjee, Arnab
dc.contributor.authorNagle, Advait
dc.contributor.authorStasiak, Marcin
dc.contributor.authorCharman, Susan A
dc.contributor.authorAngulo-Barturen, Inigo
dc.contributor.authorFerrer, Santiago
dc.contributor.authorBelen Jimenez-Diaz, Maria
dc.contributor.authorSantos Martinez, Maria
dc.contributor.authorJavier Gamo, Francisco
dc.contributor.authorAvery, Vicky M
dc.contributor.authorRuecker, Andrea
dc.contributor.authorDelves, Michael
dc.contributor.authorKirk, Kiaran
dc.contributor.authorBerriman, Matthew
dc.contributor.authorKortagere, Sandhya
dc.contributor.authorBurrows, Jeremy
dc.contributor.authorFan, Erkang
dc.contributor.authorBergman, Lawrence W
dc.date.accessioned2017-09-15T04:36:07Z
dc.date.available2017-09-15T04:36:07Z
dc.date.issued2014
dc.identifier.issn2041-1723
dc.identifier.doi10.1038/ncomms6521
dc.identifier.urihttp://hdl.handle.net/10072/124827
dc.description.abstractThe quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na+ regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na+ homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na+ homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherNature Publishing Group
dc.publisher.placeUnited Kingdom
dc.relation.ispartofpagefrom5521-1
dc.relation.ispartofpageto5521-10
dc.relation.ispartofjournalNature Communications
dc.relation.ispartofvolume5
dc.subject.fieldofresearchMedicinal and biomolecular chemistry not elsewhere classified
dc.subject.fieldofresearchcode340499
dc.titlePyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dcterms.licensehttp://creativecommons.org/licenses/by/4.0/
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© The Author(s) 2014. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
gro.hasfulltextFull Text
gro.griffith.authorAvery, Vicky M.


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