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

LaMonte, GM; Rocamora, F; Marapana, DS; Gnadig, NF; Ottilie, S; Luth, MR; Worgall, TS; Goldgof, GM; Mohunlal, R; Santha Kumar, TR; Thompson, JK; Vigil, E; Yang, J; Hutson, D; Johnson, T; Huang, J; Williams, RM; Zou, BY; Cheung, AL; Kumar, P; Egan, TJ; Lee, MCS; Siegel, D; Cowman, AF; Fidock, DA; Winzeler, EA

Author(s): LaMonte, GM; Rocamora, F; Marapana, DS; Gnadig, NF; Ottilie, S; Luth, MR; Worgall, TS; Goldgof, GM; Mohunlal, R; Santha Kumar, TR; Thompson, JK; Vigil, E; Yang, J; Hutson, D; Johnson, T; Huang, J; Williams, RM; Zou, BY; Cheung, AL; Kumar, P; Egan, TJ; Lee, MCS; Siegel, D; Cowman, AF; Fidock, DA; Winzeler, EA;
Details: Publication Year 2020-04-14,Volume 11,Issue #1,Page 1780
Journal Title: Nature Communications
Publication Type: Journal Article
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.
Publisher: NPG
Research Division(s): Infectious Diseases And Immune Defence
PubMed ID: 32286267
Publisher's Version: https://doi.org/10.1038/s41467-020-15440-4
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-020-15440-4
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2020-05-04 09:07:10

Last Modified: 2020-05-04 10:11:24