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

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 A 2 (PLA 2) activity. Inhibition of PRDX6 with a PLA 2 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 host-derived drug target for development of antimalarial drugs that could help overcome artemisinin resistance. [Display omitted] • Human peroxiredoxin 6 (PRDX6) is internalized by P. falciparum blood stages • Inhibition of host PRDX6 causes lethal lipid-peroxidation damage in the parasite • Co-treatment with artemisinin and PRDX6 inhibitors overcomes artemisinin resistance • Targeting of a host enzyme like PRDX6 may prevent development of drug resistance Wagner et al. find that Plasmodium falciparum blood stages internalize human PRDX6, which repairs lipid-peroxidation damage. PRDX6 inhibitors prevent lipid repair and kill the parasite. Co-treatment of artemisinin-resistant strains with PRDX6 inhibitors and artemisinin restores susceptibility to artemisinin. PRDX6 thus provides a promising host-based target for anti-malaria drug development. [ABSTRACT FROM AUTHOR]