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Treatment of erythrocytes with the 2-Cys peroxiredoxin inhibitor, conoidin A, prevents the growth of Plasmodium falciparum and enhances parasite sensitivity to chloroquine

Citation

Brizuela, M and Huang, HM and Smith, C and Burgio, G and Foote, SJ and McMorran, BJ, Treatment of erythrocytes with the 2-Cys peroxiredoxin inhibitor, conoidin A, prevents the growth of Plasmodium falciparum and enhances parasite sensitivity to chloroquine, PLoS ONE, 9, (4) Article e92411. ISSN 1932-6203 (2014) [Refereed Article]


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Copyright 2014 The Authors-distributed under the terms of the Creative Commons Attribution License, (CC BY-NC-ND 3.0 AU) which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

DOI: doi:10.1371/journal.pone.0092411

Abstract

The human erythrocyte contains an abundance of the thiol-dependant peroxidase Peroxiredoxin-2 (Prx2), which protects the cell from the pro-oxidant environment it encounters during its 120 days of life in the blood stream. In malarial infections, the Plasmodium parasite invades red cells and imports Prx2 during intraerythrocytic development, presumably to supplement in its own degradation of peroxides generated during cell metabolism, especially hemoglobin (Hb) digestion. Here we demonstrate that an irreversible Prx2 inhibitor, Conoidin A (2,3-bis(bromomethyl)-1,4-dioxide-quinoxaline; BBMQ), has potent cytocidal activity against cultured P. falciparum. Parasite growth was also inhibited in red cells that were treated with BBMQ and then washed prior to parasite infection. These cells remained susceptible to merozoite invasion, but failed to support normal intraerythrocytic development. In addition the potency of chloroquine (CQ), an antimalarial drug that prevents the detoxification of Hb-derived heme, was significantly enhanced in the presence of BBMQ. CQ IC 50 values decreased an order of magnitude when parasites were either co-incubated with BBMQ, or introduced into BBMQ-pretreated cells; these effects were equivalent for both drug-resistant and drug-sensitive parasite lines. Together these results indicate that treatment of red cells with BBMQ renders them incapable of supporting parasite growth and increases parasite sensitivity to CQ. We also propose that molecules such as BBMQ that target host cell proteins may constitute a novel host-directed therapeutic approach for treating malaria. © 2014 Brizuela et al.

Item Details

Item Type:Refereed Article
Research Division:Biological Sciences
Research Group:Biochemistry and Cell Biology
Research Field:Biochemistry and Cell Biology not elsewhere classified
Objective Division:Environment
Objective Group:Control of Pests, Diseases and Exotic Species
Objective Field:Control of Pests, Diseases and Exotic Species not elsewhere classified
Author:Brizuela, M (Mrs Mariana Brizuela)
Author:Smith, C (Dr Clare Smith)
ID Code:91742
Year Published:2014
Web of Science® Times Cited:9
Deposited By:Menzies Institute for Medical Research
Deposited On:2014-05-29
Last Modified:2015-01-27
Downloads:204 View Download Statistics

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