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Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum

Vaidya, Akhil B., Morrisey, Joanne M., Zhang, Zhongsheng, Das, Sudipta, Daly, Thomas M., Otto, Thomas D., Spillman, Natalie J., Wyvratt, Matthew, Siegl, Peter, Marfurt, Jutta, Wirjanata, Grennady, Sebayang, Boni F., Price, Ric N., Chatterjee, Arnab, Nagle, Advait, Stasiak, Marcin, Charman, Susan A., Angulo-Barturen, Inigo, Ferrer, Santiago and Jimenez-Diaz, Maria Belen (2014). Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum. Nature Communications,5(Articel No. 5521).

Document type: Journal Article
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IRMA ID 84473306xPUB55
NHMRC Grant No. 585473
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Title Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum
Author Vaidya, Akhil B.
Morrisey, Joanne M.
Zhang, Zhongsheng
Das, Sudipta
Daly, Thomas M.
Otto, Thomas D.
Spillman, Natalie J.
Wyvratt, Matthew
Siegl, Peter
Marfurt, Jutta
Wirjanata, Grennady
Sebayang, Boni F.
Price, Ric N.
Chatterjee, Arnab
Nagle, Advait
Stasiak, Marcin
Charman, Susan A.
Angulo-Barturen, Inigo
Ferrer, Santiago
Jimenez-Diaz, Maria Belen
Journal Name Nature Communications
Publication Date 2014
Volume Number 5
Issue Number Articel No. 5521
ISSN 2041-1723   (check CDU catalogue open catalogue search in new window)
Scopus ID 2-s2.0-84923311088
Total Pages 10
Place of Publication United Kingdom
Publisher Nature Publishing Group
HERDC Category C1 - Journal Article (DIISR)
Abstract The 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.
DOI http://dx.doi.org/10.1038/ncomms6521   (check subscription with CDU E-Gateway service for CDU Staff and Students  check subscription with CDU E-Gateway in new window)
Additional Notes This is an Open Access article distributed under the terms of the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Description for Link Link to CC Attribution 4.0 License
URL https://creativecommons.org/licenses/by/4.0/au


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