Antimalarial NADPH-Consuming Redox-Cyclers As Superior Glucose-6-Phosphate Dehydrogenase Deficiency Copycats

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BIELITZA, Max, BELORGEY, Didier, EHRHARDT, Katharina, JOHANN, Laure, LANFRANCHI, Don Antoine, GALLO, Valentina, SCHWARZER, Evelin, MOHRING, Franziska, JORTZIK, Esther, WILLIAMS, David L., BECKER, Katja, ARESE, Paolo, ELHABIRI, Mourad et DAVIOUD-CHARVET, Elisabeth, 2015. Antimalarial NADPH-Consuming Redox-Cyclers As Superior Glucose-6-Phosphate Dehydrogenase Deficiency Copycats. Antioxidants and Redox Signaling [en ligne]. 2015. Vol. 22, n° 15pp. 1337-1351. [Consultésans date]. DOI 10.1089/ars.2014.6047. Consulté de : http://online.liebertpub.com/doi/pdfplus/10.1089/ars.2014.6047
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Auteurs Max Bielitza
Didier Belorgey
Katharina Ehrhardt
Laure Johann
Don Lanfranchi
Valentina Gallo
Evelin Schwarzer
Franziska Mohring
Esther Jortzik
David Williams
Katja Becker
Paolo Arese
Mourad Elhabiri
Elisabeth Davioud-Charvet
Unité de recherche du site Laboratoire de Chimie Moléculaire - LCM - UMR7509
Langue

en
Volume

22
Numéro

15
Page de début

1337
Page de fin

1351
Date de première publication

2015
ISSN

1523-0864
Titre de la source (revue, livre…)

Antioxidants and Redox Signaling
Résumé

Aims: Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes parasitized by Plasmodium falciparum were shown to protect G6PD-deficient populations from severe malaria. Here, we investigated the mechanism of a novel
Show moreAims: Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes parasitized by Plasmodium falciparum were shown to protect G6PD-deficient populations from severe malaria. Here, we investigated the mechanism of a novel antimalarial series, namely 3-[substituted-benzyl]-menadiones, to understand whether these NADPH-consuming redox-cyclers, which induce oxidative stress, mimic the natural protection of G6PD deficiency. Results: We demonstrated that the key benzoylmenadione metabolite of the lead compd. acts as an efficient redox-cycler in NADPH-dependent metHb redn., leading to the continuous formation of reactive oxygen species, ferrylHb, and subsequent hemichrome pptn. Structure-activity relationships evidenced that both drug metabolites and Hb catabolites contribute to potentiate drug effects and inhibit parasite development. Disruption of redox homeostasis by the lead benzylmenadione was specifically induced in Plasmodium falciparum parasitized erythrocytes and not in non-infected cells, and was visualized via changes in the glutathione redox potential of living parasite cytosols. Furthermore, the redox-cycler shows additive and synergistic effects in combination with compds. affecting the NADPH flux in vivo. Innovation: The lead benzylmenadione 1c is the first example of a novel redox-active agent that mimics the behavior of a falciparum parasite developing inside a G6PD-deficient red blood cell (RBC) giving rise to malaria protection, and it exerts specific additive effects that are inhibitory to parasite development, without harm for non-infected G6PD-sufficient or -deficient RBCs. Conclusion: This strategy offers an innovative perspective for the development of future antimalarial drugs for G6PD-sufficient and -deficient populations. Antioxid. Redox Signal. 22, 1337-1352.
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DOI 10.1089/ars.2014.6047
Éditeur

Mary Ann Liebert
Éditeur

Mary Ann Liebert, Inc.
URL éditeur http://online.liebertpub.com/doi/pdfplus/10.1089/ars.2014.6047
Type de publication

journal article
Type de publication

ACL
Fonction

ctb
aut
URL https://univoak.eu/islandora/object/islandora:54467