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Targeting Plasmodium PI(4)K to eliminate malaria

Author

Listed:
  • Case W. McNamara

    (Genomics Institute of the Novartis Research Foundation)

  • Marcus C. S. Lee

    (Columbia University Medical Center)

  • Chek Shik Lim

    (Novartis Institutes for Tropical Disease, 138670 Singapore)

  • Siau Hoi Lim

    (Novartis Institutes for Tropical Disease, 138670 Singapore)

  • Jason Roland

    (Genomics Institute of the Novartis Research Foundation)

  • Advait Nagle

    (Genomics Institute of the Novartis Research Foundation)

  • Oliver Simon

    (Novartis Institutes for Tropical Disease, 138670 Singapore)

  • Bryan K. S. Yeung

    (Novartis Institutes for Tropical Disease, 138670 Singapore)

  • Arnab K. Chatterjee

    (Genomics Institute of the Novartis Research Foundation)

  • Susan L. McCormack

    (Genomics Institute of the Novartis Research Foundation)

  • Micah J. Manary

    (School of Medicine, University of California, San Diego, La Jolla, California 92093, USA)

  • Anne-Marie Zeeman

    (Biomedical Primate Research Centre, PO Box 3306, 2280 GH Rijswijk, The Netherlands)

  • Koen J. Dechering

    (TropIQ Health Sciences, 6525 GA Nijmegen, The Netherlands)

  • T. R. Santha Kumar

    (Columbia University Medical Center)

  • Philipp P. Henrich

    (Columbia University Medical Center)

  • Kerstin Gagaring

    (Genomics Institute of the Novartis Research Foundation)

  • Maureen Ibanez

    (Genomics Institute of the Novartis Research Foundation)

  • Nobutaka Kato

    (Genomics Institute of the Novartis Research Foundation)

  • Kelli L. Kuhen

    (Genomics Institute of the Novartis Research Foundation)

  • Christoph Fischli

    (Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland)

  • Matthias Rottmann

    (Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland
    University of Basel, CH-4003 Basel, Switzerland)

  • David M. Plouffe

    (Genomics Institute of the Novartis Research Foundation)

  • Badry Bursulaya

    (Genomics Institute of the Novartis Research Foundation)

  • Stephan Meister

    (School of Medicine, University of California, San Diego, La Jolla, California 92093, USA)

  • Lucia Rameh

    (School of Medicine, Boston University)

  • Joerg Trappe

    (Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland)

  • Dorothea Haasen

    (Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland)

  • Martijn Timmerman

    (TropIQ Health Sciences, 6525 GA Nijmegen, The Netherlands)

  • Robert W. Sauerwein

    (TropIQ Health Sciences, 6525 GA Nijmegen, The Netherlands
    Radboud University, Nijmegen Medical CentrePO Box 9101, 6500 HB Nijmegen, The Netherlands)

  • Rossarin Suwanarusk

    (Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Biopolis, 138648 Singapore)

  • Bruce Russell

    (Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Biopolis, 138648 Singapore
    Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, 117545 Singapore)

  • Laurent Renia

    (Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Biopolis, 138648 Singapore)

  • Francois Nosten

    (Centre for Tropical Medicine, University of Oxford, Oxford OX3 7BN, UK
    Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot 63110, Thailand)

  • David C. Tully

    (Genomics Institute of the Novartis Research Foundation)

  • Clemens H. M. Kocken

    (Biomedical Primate Research Centre, PO Box 3306, 2280 GH Rijswijk, The Netherlands)

  • Richard J. Glynne

    (Genomics Institute of the Novartis Research Foundation)

  • Christophe Bodenreider

    (Novartis Institutes for Tropical Disease, 138670 Singapore)

  • David A. Fidock

    (Columbia University Medical Center
    Columbia University Medical Center)

  • Thierry T. Diagana

    (Novartis Institutes for Tropical Disease, 138670 Singapore)

  • Elizabeth A. Winzeler

    (Genomics Institute of the Novartis Research Foundation
    School of Medicine, University of California, San Diego, La Jolla, California 92093, USA)

Abstract

Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.

Suggested Citation

  • Case W. McNamara & Marcus C. S. Lee & Chek Shik Lim & Siau Hoi Lim & Jason Roland & Advait Nagle & Oliver Simon & Bryan K. S. Yeung & Arnab K. Chatterjee & Susan L. McCormack & Micah J. Manary & Anne-, 2013. "Targeting Plasmodium PI(4)K to eliminate malaria," Nature, Nature, vol. 504(7479), pages 248-253, December.
    • Handle: RePEc:nat:nature:v:504:y:2013:i:7479:d:10.1038_nature12782
    DOI: 10.1038/nature12782
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    Cited by:

    1. Nor Diyana Dian & Mohd Amirul Fitri A. Rahim & Sherwin Chan & Zulkarnain Md Idris, 2022. "Non-Human Primate Malaria Infections: A Review on the Epidemiology in Malaysia," IJERPH, MDPI, vol. 19(13), pages 1-17, June.
    2. Mariska Naude & Ashleigh van Heerden & Janette Reader & Mariëtte van der Watt & Jandeli Niemand & Dorè Joubert & Giulia Siciliano & Pietro Alano & Mathew Njoroge & Kelly Chibale & Esperanza Herreros &, 2024. "Eliminating malaria transmission requires targeting immature and mature gametocytes through lipoidal uptake of antimalarials," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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