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Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway

Author

Listed:
  • Gregory M. LaMonte

    (University of California, San Diego)

  • Frances Rocamora

    (University of California, San Diego)

  • Danushka S. Marapana

    (Division of Infection and Immunity, Walter and Eliza Hall Institute for Medical Research
    University of Melbourne)

  • Nina F. Gnädig

    (Columbia University Irving Medical Center)

  • Sabine Ottilie

    (University of California, San Diego)

  • Madeline R. Luth

    (University of California, San Diego)

  • Tilla S. Worgall

    (Columbia University Irving Medical Center)

  • Gregory M. Goldgof

    (University of California, San Diego
    University of California)

  • Roxanne Mohunlal

    (Columbia University Irving Medical Center
    University of Cape Town)

  • T. R. Santha Kumar

    (Columbia University Irving Medical Center)

  • Jennifer K. Thompson

    (Division of Infection and Immunity, Walter and Eliza Hall Institute for Medical Research
    University of Melbourne)

  • Edgar Vigil

    (University of California, San Diego)

  • Jennifer Yang

    (University of California, San Diego)

  • Dylan Hutson

    (University of California, San Diego)

  • Trevor Johnson

    (University of California, San Diego)

  • Jianbo Huang

    (University of California, San Diego)

  • Roy M. Williams

    (University of California, San Diego)

  • Bing Yu Zou

    (University of California, San Diego)

  • Andrea L. Cheung

    (University of California, San Diego)

  • Prianka Kumar

    (University of California, San Diego)

  • Timothy J. Egan

    (University of Cape Town
    University of Cape Town)

  • Marcus C. S. Lee

    (Parasites and Microbes Programme, Wellcome Sanger Institute)

  • Dionicio Siegel

    (University of California, San Diego)

  • Alan F. Cowman

    (Division of Infection and Immunity, Walter and Eliza Hall Institute for Medical Research
    University of Melbourne)

  • David A. Fidock

    (Columbia University Irving Medical Center
    Columbia University Irving Medical Center)

  • Elizabeth A. Winzeler

    (University of California, San Diego)

Abstract

A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models. But despite the identification of resistance mechanisms in P. falciparum, the mode of action of IZPs remains unknown. To investigate, we here combine in vitro evolution and genome analysis in Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods in P. falciparum. Our findings reveal that IZP-resistant S. cerevisiae clones carry mutations in genes involved in Endoplasmic Reticulum (ER)-based lipid homeostasis and autophagy. In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing.

Suggested Citation

  • Gregory M. LaMonte & Frances Rocamora & Danushka S. Marapana & Nina F. Gnädig & Sabine Ottilie & Madeline R. Luth & Tilla S. Worgall & Gregory M. Goldgof & Roxanne Mohunlal & T. R. Santha Kumar & Jenn, 2020. "Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15440-4
    DOI: 10.1038/s41467-020-15440-4
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    Cited by:

    1. 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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