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PLoS Pathog. 2019 Jun 6;15(6):e1007722. doi: 10.1371/journal.ppat.1007722. eCollection 2019 Jun.

Covalent Plasmodium falciparum-selective proteasome inhibitors exhibit a low propensity for generating resistance in vitro and synergize with multiple antimalarial agents.

Author information

1
Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, United States of America.
2
Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States of America.
3
Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, School of Medicine, San Diego, CA, United States of America.
4
MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, United Kingdom.
5
Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, United States of America.

Abstract

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 <five-fold decreases in parasite susceptibility. This result compares favorably against previously published non-covalent inhibitors of the Plasmodium proteasome that can select for resistant parasites with >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.

PMID:
31170268
DOI:
10.1371/journal.ppat.1007722
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