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

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Journal:
Nature communications, Volume: 11, Issue: 1
Published:
April 14, 2020
PMID:
32286267
Authors:
Gregory M LaMonte GM, Frances Rocamora F, Danushka S Marapana DS, Nina F Gn├Ądig NF, Sabine Ottilie S, Madeline R Luth MR, Tilla S Worgall TS, Gregory M Goldgof GM, Roxanne Mohunlal R, T R Santha Kumar TR, Jennifer K Thompson JK, Edgar Vigil E, Jennifer Yang J, Dylan Hutson D, Trevor Johnson T, Jianbo Huang J, Roy M Williams RM, Bing Yu Zou BY, Andrea L Cheung AL, Prianka Kumar P, Timothy J Egan TJ, Marcus C S Lee MCS, Dionicio Siegel D, Alan F Cowman AF, David A Fidock DA, Elizabeth A Winzeler EA
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.