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bioRxiv · 10.1101/2022.04.11.487889

Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target

Wagner, M. P.·Formaglio, P.·Gorgette, O.·Dziekan, J. M.·Huon, C.·Berneburg, I.·Rahlfs, S.·Barale, J.-C.·Feinstein, S. I.·Fisher, A. B.·Menard, D.·Bozdech, Z.·Amino, R.·Touqui, L.·Chitnis, C. E.
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Abstract

The uptake and digestion of host hemoglobin by malaria parasites during blood stage growth leads to significant oxidative damage of membrane lipids. Repair of lipid peroxidation damage is crucial for parasite survival. Here, we demonstrate that Plasmodium falciparum imports a host antioxidant enzyme, peroxiredoxin 6 (PRDX6), during hemoglobin uptake from the red blood cell cytosol. PRDX6 is a lipid peroxidation repair enzyme with phospholipase A2 (PLA2) activity. Inhibition of PRDX6 with a PLA2 inhibitor, Darapladib, increases lipid peroxidation damage in the parasite and disrupts transport of hemoglobin-containing vesicles to the food vacuole, causing parasite death. Furthermore, inhibition of PRDX6 synergistically reduces the survival of artemisinin-resistant parasites following co-treatment of parasite cultures with artemisinin and Darapladib. Thus, PRDX6 is a unique host-derived drug target for development of antimalarial drugs that could help overcome artemisinin resistance. GRAPHICAL ABSTRACT O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

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Wagner, M. P., Formaglio, P., Gorgette, O., Dziekan, J. M., Huon, C., Berneburg, I., Rahlfs, S., Barale, J.-C., Feinstein, S. I., Fisher, A. B., Menard, D., Bozdech, Z., Amino, R., Touqui, L., Chitnis, C. E.. 2022-04-11. Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target. https://doi.org/10.1101/2022.04.11.487889

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