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

Blackman, M. J. et al. (2019) Covalent Plasmodium falciparum-selective proteasome inhibitors exhibit a low propensity for generating resistance in vitro and synergize with multiple antimalarial agents. PLoS Pathogens, 15(6), e1007722. (doi: 10.1371/journal.ppat.1007722) (PMID:31170268) (PMCID:PMC6553790)

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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.

Item Type:Articles
Additional Information:Funding for this work was provided in part by the National Institutes of Health: R21 AI127581 (to M.B. and D.A.F.), R01 AI109023 and AI124678 (to D.A.F.), and R21 AI137900 (to C.L.N.). B.H.S. gratefully acknowledges support from T32 AI106711 (PD: D. Fidock). M.R.L. gratefully acknowledges support from T32 GM008666 (PD: L. Goldstein). P.A. and P.C.A.dF. acknowledge support from the UK Medical Research Council: grant MC_UP_1201/5.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:da Fonseca, Professor Paula
Authors: Blackman, M. J., Stokes, B. H., Yoo, E., Murithi, J. M., Luth, M. R., Afanasyev, P., da Fonseca, P. C.A., Winzeler, E. A., Ng, C. L., Bogyo, M., and Fidock, D. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7366
ISSN (Online):1553-7374
Copyright Holders:Copyright © 2019 Stokes et al.
First Published:First published in PLoS Pathogens 15(6):e1007722
Publisher Policy:Reproduced under a Creative Commons licence

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