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

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.

• Authors: 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, Elizabeth A Winzeler
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 1780 (04 14 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32286267 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antimalarials
• Protozoan Proteins
• Pyrazoles

Topics

• Antimalarials (pharmacology)
• Chromatography, High Pressure Liquid
• Endoplasmic Reticulum (drug effects, metabolism)
• Inhibitory Concentration 50
• Mass Spectrometry
• Plasmodium falciparum (drug effects)
• Protozoan Proteins (metabolism)
• Pyrazoles (pharmacology)
• Saccharomyces cerevisiae (drug effects, metabolism)
• Secretory Pathway (drug effects)