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Covalent Plasmodium falciparum-selective proteasome inhibitors exhibit a low propensity for generating resistance in vitro and synergize with multiple antimalarial agents
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Covalent Plasmodium falciparum-selective proteasome inhibitors exhibit a low propensity for generating resistance in vitro and synergize with multiple antimalarial agents
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Journal Article
Covalent Plasmodium falciparum-selective proteasome inhibitors exhibit a low propensity for generating resistance in vitro and synergize with multiple antimalarial agents
2019
Overview
Therapeutics with novel modes of action and a low risk of generating resistance are urgently needed to combat drug-resistant Plasmodium falciparum malaria. Here, we report that the peptide vinyl sulfones WLL-vs (WLL) and WLW-vs (WLW), highly selective covalent inhibitors of the P. falciparum proteasome, potently eliminate genetically diverse parasites, including K13-mutant, artemisinin-resistant lines, and are particularly active against ring-stage parasites. Selection studies reveal that parasites do not readily acquire resistance to WLL or WLW and that mutations in the β2, β5 or β6 subunits of the 20S proteasome core particle or in components of the 19S proteasome regulatory particle yield only hundred-fold decreases in susceptibility. We observed no cross-resistance between WLL and WLW. Moreover, most mutations that conferred a modest loss of parasite susceptibility to one inhibitor significantly increased sensitivity to the other. These inhibitors potently synergized multiple chemically diverse classes of antimalarial agents, implicating a shared disruption of proteostasis in their modes of action. These results underscore the potential of targeting the Plasmodium proteasome with covalent small molecule inhibitors as a means of combating multidrug-resistant malaria.
Publisher
Public Library of Science,Public Library of Science (PLoS)
Subject
/ Antimalarials - pharmacology
/ Drug Resistance - drug effects
/ Funding
/ Genomes
/ Humans
/ Malaria
/ Medicine
/ Medicine and Health Sciences
/ Mutation
/ Novels
/ Peptides
/ Plasmodium falciparum - enzymology
/ Plasmodium falciparum - genetics
/ Proteasome Endopeptidase Complex - metabolism
/ Proteasome Inhibitors - chemistry
/ Proteasome Inhibitors - pharmacology
/ Proteins
/ Protozoan Proteins - antagonists & inhibitors
/ Protozoan Proteins - genetics
/ Protozoan Proteins - metabolism
/ Software
/ Sulfones
