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. 2022 Jun 14;39(11):110923.
doi: 10.1016/j.celrep.2022.110923.

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

Matthias Paulus Wagner  1 , Pauline Formaglio  2 , Olivier Gorgette  3 , Jerzy Michal Dziekan  4 , Christèle Huon  1 , Isabell Berneburg  5 , Stefan Rahlfs  5 , Jean-Christophe Barale  6 , Sheldon I Feinstein  7 , Aron B Fisher  8 , Didier Ménard  9 , Zbynek Bozdech  4 , Rogerio Amino  2 , Lhousseine Touqui  10 , Chetan E Chitnis  11
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Free article

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

Matthias Paulus Wagner et al. Cell Rep. .
Free article

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 host-derived drug target for development of antimalarial drugs that could help overcome artemisinin resistance.

Keywords: CP: Metabolism; CP: Microbiology; PRDX6; Plasmodium falciparum; artemisinin; endocytosis; hemoglobin; host cell cytosol uptake; lipid peroxidation; malaria; molecular parasitology; oxidative stress.

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Conflict of interest statement

Declaration of interests A patent application has been filed by Institut Pasteur based on the results of this publication with M.P.W., C.E.C., L.T., O.G., C.H., P.F., and R.H. as inventors. A.B.F. and S.I.F. are shareholders in Peroxitech, Inc., a USA company that is developing a peptide-based PRDX6 inhibitor as a therapeutic agent.

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