Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum
Year: 2014
Type: article
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.
Source: Nature Communications
DOI: 10.1038/ncomms6521
Authors: 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
Institutions: Drexel University, University of Washington, Wellcome Sanger Institute, Australian National University, Medicines for Malaria Venture, Charles Darwin University, Menzies School of Health Research, Eijkman Institute for Molecular Biology, University of Oxford, Genomics Institute of the Novartis Research Foundation, Monash University, GlaxoSmithKline (Spain), Griffith University, Imperial College London
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $6,990
Funders: Drexel University, Wellcome Trust, Menzies School of Health Research, Medicines for Malaria Venture, National Institutes of Health, College of Medicine, Drexel University, Medical Research Council, National Health and Medical Research Council, National Institute of Allergy and Infectious Diseases
Awards: G1093531541, Targeting an ion pump in the malaria parasite, G119964413, G1924830673, Exported epoxide hydrolases of the malaria parasite, Plasmodium falciparum, and their role in modulation of host vasoregulation, G2973790809, G4612446324, G4839860845, Plasmodium Invasion Machinery, Molecular Pathways Targeted by Potent Antimalarial Pyrazole Compounds, Ion regulation in the malaria parasite, Optimising antimalarial combination therapies in an area coendemic for vivax and falciparum malaria., Wellcome Trust Sanger Institute - generic account for deposition of all core- funded research papers, G8948955750, Mitochondrial Functions in Malaria Parasites
OpenAlex ID: W1999044153