Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway.
Antimalarials
/ pharmacology
Chromatography, High Pressure Liquid
Endoplasmic Reticulum
/ drug effects
Inhibitory Concentration 50
Mass Spectrometry
Plasmodium falciparum
/ drug effects
Protozoan Proteins
/ metabolism
Pyrazoles
/ pharmacology
Saccharomyces cerevisiae
/ drug effects
Secretory Pathway
/ drug effects
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
14 04 2020
14 04 2020
Historique:
received:
25
06
2019
accepted:
01
03
2020
entrez:
15
4
2020
pubmed:
15
4
2020
medline:
25
7
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32286267
doi: 10.1038/s41467-020-15440-4
pii: 10.1038/s41467-020-15440-4
pmc: PMC7156427
doi:
Substances chimiques
Antimalarials
0
Protozoan Proteins
0
Pyrazoles
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1780Subventions
Organisme : NIGMS NIH HHS
ID : T32 GM008666
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI090141
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : R01 AI103058
Pays : United States
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