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

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, Jennifer K. Thompson, Edgar Vigil, Jennifer Yang, Dylan Hutson, Trevor Johnson, Jianbo Huang, Roy M. Williams, Bing Yu Zou, Andrea L. Cheung, Prianka KumarTimothy J. Egan, Marcus C.S. Lee, Dionicio Siegel, Alan F. Cowman, David A. Fidock, Elizabeth A. Winzeler (Lead / Corresponding author)

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21 Citations (Scopus)
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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.

Original languageEnglish
Article number1780
Number of pages15
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 14 Apr 2020

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General
  • General Physics and Astronomy

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