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Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway by LaMonte, Gregory M.; Rocamora, Frances; Marapana, Danushka S.; Gnädig, Nina F.; Ottilie, Sabine; Luth, Madeline R.; Worgall, Tilla S.; Goldgof, Gregory M.; Mohunlal, Roxanne; Santha Kumar, T. R.; Thompson, Jennifer K.; Vigil, Edgar; Yang, Jennifer; Hutson, Dylan; Johnson, Trevor; Huang, Jianbo; Williams, Roy M.; Zou, Bing Yu; Cheung, Andrea L.; Kumar, Prianka; Egan, Timothy J.; Lee, Marcus C. S.; Siegel, Dionicio; Cowman, Alan F.; Fidock, David A.; Winzeler, Elizabeth A. is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

What is Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway about?

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.

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Author

LaMonte, Gregory M.; Rocamora, Frances; Marapana, Danushka S.; Gnädig, Nina F.; Ottilie, Sabine; Luth, Madeline R.; Worgall, Tilla S.; Goldgof, Gregory M.; Mohunlal, Roxanne; Santha Kumar, T. R.; Thompson, Jennifer K.; Vigil, Edgar; Yang, Jennifer; Hutson, Dylan; Johnson, Trevor; Huang, Jianbo; Williams, Roy M.; Zou, Bing Yu; Cheung, Andrea L.; Kumar, Prianka; Egan, Timothy J.; Lee, Marcus C. S.; Siegel, Dionicio; Cowman, Alan F.; Fidock, David A.; Winzeler, Elizabeth A.

Publisher

Nature Publishing Group; Springer Science and Business Media LLC; [London]: Nature Publishing Group, 2010-; Society for Mining, Metallurgy and Exploration Inc.; Research Square (ISSN 2041-1723)

Published

2020

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)