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

Mariana Brizuela, Hong Ming Huang, Clare Smith, Gaétan Burgio, Simon J. Foote, Brendan J. McMorran

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

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.

Original languageEnglish
Article numbere92411
Number of pages9
JournalPLoS One
Volume9
Issue number4
DOIs
Publication statusPublished - 3 Apr 2014
Externally publishedYes

Bibliographical note

© 2014 Brizuela et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Keywords

  • Parasitic diseases
  • red blood cells
  • plasmodium
  • malarial parasites
  • trophozoites
  • antimalarials
  • chloroquine
  • host cells

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