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 IC50 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.
Highlights
Infections by the malaria parasite, Plasmodium falciparum, account for almost one million deaths each year
BBMQ pretreated red cells Uninfected red cells were treated with BBMQ for 24 hours in cell culture medium (CCM)-wash at 4uC with constant mixing
We have shown that treatment of red cells with an irreversible inhibitor of 2-Cys peroxiredoxins, BBMQ, prevents the growth of P. falciparum and enhances the sensitivity of the parasite to CQ
Summary
Infections by the malaria parasite, Plasmodium falciparum, account for almost one million deaths each year. Efforts to reduce the burden of disease are hampered by the development of drugresistant strains [1]. Chloroquine (CQ) in particular was once a highly effective and mainstay treatment, but is virtually useless in most parts of the world. The drug is understood to kill the parasite growing inside the red blood cell by targeting the hemoglobin digestion pathway in the parasite food vacuole. The drug inhibits the conversion of heme to hemozoin. The build-up of heme generates free radicals and oxidative molecules, including peroxides, which are toxic to the cell [2]. Many parasite strains throughout the world are insensitive to CQ treatment due to acquisition of variant drug transporter proteins that expel the drug from the parasite and provide a selective advantage under CQ exposure [3,4]
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