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

Akhil B Vaidya; Joanne M Morrisey; Zhongsheng Zhang; Sudipta Das; Thomas M Daly; Thomas D Otto; Natalie J Spillman; Matthew Wyvratt; Peter Siegl; Jutta Marfurt; Grennady Wirjanata; Boni F Sebayang; Ric N Price; Arnab Chatterjee; Advait Nagle; Marcin Stasiak; Susan A Charman; Iñigo Angulo-Barturen; Santiago Ferrer; María Belén Jiménez-Díaz; María Santos Martínez; Francisco Javier Gamo; Vicky M Avery; Andrea Ruecker; Michael Delves; Kiaran Kirk; Matthew Berriman; Sandhya Kortagere; Jeremy Burrows; Erkang Fan; Lawrence W Bergman

doi:10.1038/ncomms6521

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

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

Akhil B Vaidya, Joanne M Morrisey, Zhongsheng Zhang, Sudipta Das, Thomas M Daly, Thomas D Otto, Natalie J Spillman, Matthew Wyvratt, Peter Siegl, Jutta Marfurt, …

Nature communications, v 5(1), pp 5521-5521

25 Nov 2014

DOI: https://doi.org/10.1038/ncomms6521

PMID: 25422853

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Abstract

Adenosine Triphosphatases - genetics

Adenosine Triphosphatases - metabolism

Amides - pharmacology

Antimalarials - pharmacology

Benzimidazoles - pharmacology

Erythrocytes - parasitology

Female

Homeostasis - drug effects

Humans

Malaria - parasitology

Male

Plasmodium berghei - drug effects

Plasmodium berghei - genetics

Plasmodium berghei - metabolism

Plasmodium falciparum - drug effects

Plasmodium falciparum - enzymology

Plasmodium falciparum - genetics

Plasmodium falciparum - metabolism

Protein Kinases - genetics

Protein Kinases - metabolism

Protozoan Proteins

Pyrazoles - pharmacology

Sodium - metabolism

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.

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Title: Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum
Creators: Akhil B Vaidya - Drexel University
Joanne M Morrisey - Drexel University
Zhongsheng Zhang - University of Washington
Sudipta Das - Drexel University
Thomas M Daly - Drexel University
Thomas D Otto - Wellcome Sanger Institute
Natalie J Spillman - Australian National University
Matthew Wyvratt - Medicines for Malaria Venture
Peter Siegl - Medicines for Malaria Venture
Jutta Marfurt - Menzies School of Health Research
Grennady Wirjanata - Menzies School of Health Research
Boni F Sebayang - Eijkman Institute for Molecular Biology
Ric N Price - Charles Darwin University
Arnab Chatterjee - Genomics Institute of the Novartis Research Foundation
Advait Nagle - Genomics Institute of the Novartis Research Foundation
Marcin Stasiak - University of Washington
Susan A Charman - Monash University, Parkville campus
Iñigo Angulo-Barturen - GlaxoSmithKline
Santiago Ferrer - GlaxoSmithKline
María Belén Jiménez-Díaz - GlaxoSmithKline, Malaria Support Group, Calle Severo Ochoa 2, Tres Cantos 28760, Spain
María Santos Martínez - GlaxoSmithKline
Francisco Javier Gamo - GlaxoSmithKline
Vicky M Avery - Griffith University
Andrea Ruecker - Imperial College London
Michael Delves - Imperial College London
Kiaran Kirk - Australian National University
Matthew Berriman - Wellcome Sanger Institute
Sandhya Kortagere - Drexel University
Jeremy Burrows - Medicines for Malaria Venture
Erkang Fan - University of Washington
Lawrence W Bergman - Drexel University
Publication Details: Nature communications, v 5(1), pp 5521-5521
Publisher: Springer Nature
Grant note: 098051 / Wellcome Trust R01 AI098413 / NIAID NIH HHS R01 AI068137 / NIAID NIH HHS 091625 / Wellcome Trust R01 AI028398 / NIAID NIH HHS WT 098051 / Wellcome Trust
Resource Type: Journal article
Language: English
Academic Unit: Microbiology and Immunology
Web of Science ID: WOS:000345913300006
Scopus ID: 2-s2.0-84923311088
Other Identifier: 991019168863604721

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Web of Science research areas: Microbiology

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

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