Pan-active Imidazolopiperazine Antimalarials Target the Plasmodium Falciparum Intracellular Secretory Pathway

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Apr 15

PMID 32286267

Citations 18

Authors

Gregory M LaMonte

Frances Rocamora

Danushka S Marapana

Nina F Gnadig

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

Affiliations

Soon will be listed here.

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.

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