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 Kumar, Timothy J. Egan, Marcus C. S. Lee, Dionicio Siegel, Alan F. Cowman, David A. Fidock and Elizabeth A. Winzeler ()
Additional contact information
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
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
Roxanne Mohunlal: Columbia University Irving Medical Center
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
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
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
David A. Fidock: Columbia University Irving Medical Center
Elizabeth A. Winzeler: University of California, San Diego

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15440-4

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