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

Author

Listed:
  • Akhil B. Vaidya

    (Center for Molecular Parasitology, Drexel University College of Medicine)

  • Joanne M. Morrisey

    (Center for Molecular Parasitology, Drexel University College of Medicine)

  • Zhongsheng Zhang

    (University of Washington)

  • Sudipta Das

    (Center for Molecular Parasitology, Drexel University College of Medicine)

  • Thomas M. Daly

    (Center for Molecular Parasitology, Drexel University College of Medicine)

  • Thomas D. Otto

    (Wellcome Trust Sanger Institute)

  • Natalie J. Spillman

    (Research School of Biology, The Australian National University)

  • Matthew Wyvratt

    (Medicines for Malaria Venture)

  • Peter Siegl

    (Medicines for Malaria Venture)

  • Jutta Marfurt

    (Menzies School of Health Research and Charles Darwin University)

  • Grennady Wirjanata

    (Menzies School of Health Research and Charles Darwin University)

  • Boni F. Sebayang

    (Eijkman Institute for Molecular Biology)

  • Ric N. Price

    (Menzies School of Health Research and Charles Darwin University
    Centre for Tropical Medicine, University of Oxford)

  • 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

    (Center for Drug Candidate Optimisation, Monash University)

  • Iñigo Angulo-Barturen

    (GlaxoSmithKline, Malaria Support Group)

  • Santiago Ferrer

    (GlaxoSmithKline, Malaria Support Group)

  • María Belén Jiménez-Díaz

    (GlaxoSmithKline, Malaria Support Group)

  • María Santos Martínez

    (GlaxoSmithKline, Malaria Support Group)

  • Francisco Javier Gamo

    (GlaxoSmithKline, Malaria Support Group)

  • Vicky M. Avery

    (Eskitis Institute, Griffith University)

  • Andrea Ruecker

    (South Kensington Campus, Imperial College)

  • Michael Delves

    (South Kensington Campus, Imperial College)

  • Kiaran Kirk

    (Research School of Biology, The Australian National University)

  • Matthew Berriman

    (Wellcome Trust Sanger Institute)

  • Sandhya Kortagere

    (Center for Molecular Parasitology, Drexel University College of Medicine)

  • Jeremy Burrows

    (Medicines for Malaria Venture)

  • Erkang Fan

    (University of Washington)

  • Lawrence W. Bergman

    (Center for Molecular Parasitology, Drexel University College of Medicine)

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.

Suggested Citation

  • 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 & Bon, 2014. "Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum," Nature Communications, Nature, vol. 5(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6521
    DOI: 10.1038/ncomms6521
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    Cited by:

    1. Deyun Qiu & Jinxin V. Pei & James E. O. Rosling & Vandana Thathy & Dongdi Li & Yi Xue & John D. Tanner & Jocelyn Sietsma Penington & Yi Tong Vincent Aw & Jessica Yi Han Aw & Guoyue Xu & Abhai K. Tripa, 2022. "A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Mario Carucci & Julien Duez & Joel Tarning & Irene García-Barbazán & Aurélie Fricot-Monsinjon & Abdoulaye Sissoko & Lucie Dumas & Pablo Gamallo & Babette Beher & Pascal Amireault & Michael Dussiot & M, 2023. "Safe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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