Abstract
The homodimeric flavoenzyme glutathione reductase catalyzes NADPH-dependent glutathione disulfide reduction. This reaction is important for keeping the redox homeostasis in human cells and in the human pathogen Plasmodium falciparum. Different types of NADPH-dependent disulfide reductase inhibitors were designed in various chemical series to evaluate the impact of each inhibition mode on the propagation of the parasites. Against malaria parasites in cultures the most potent and specific effects were observed for redox- active agents acting as subversive substrates for both glutathione reductases of the Plasmodium-infected red blood cells. In their oxidized form, these redox-active compounds are reduced by NADPH-dependent flavoenzyme-catalyzed reactions in the cytosol of infected erythrocytes. In their reduced forms, these compounds can reduce molecular oxygen to reactive oxygen species, or reduce oxidants like methemoglobin, the major nutrient of the parasite, to indigestible hemoglobin. Furthermore, studies on a fluorinated suicide-substrate of the human glutathione reductase indicate that the glutathione reductase-catalyzed bioactivation of 3-benzylnaphthoquinones to the corresponding reduced 3-benzoyl metabolites is essential for the observed antimalarial activity. In conclusion, the antimalarial lead naphthoquinones are suggested to perturb the major redox equilibria of the targeted cells. These effects result in developmental arrest of the parasite and contribute to the removal of the parasitized erythrocytes by macrophages.
Keywords: Hematin, β-hematin, antimalarial, 1, 4-naphthoquinone, NADPH-dependent glutathione reductase, redox-cycler
Current Pharmaceutical Design
Title:1,4-Naphthoquinones and Other NADPH-Dependent Glutathione Reductase- Catalyzed Redox Cyclers as Antimalarial Agents
Volume: 19 Issue: 14
Author(s): Didier Belorgey, Don Antoine Lanfranchi and Elisabeth Davioud-Charvet
Affiliation:
Keywords: Hematin, β-hematin, antimalarial, 1, 4-naphthoquinone, NADPH-dependent glutathione reductase, redox-cycler
Abstract: The homodimeric flavoenzyme glutathione reductase catalyzes NADPH-dependent glutathione disulfide reduction. This reaction is important for keeping the redox homeostasis in human cells and in the human pathogen Plasmodium falciparum. Different types of NADPH-dependent disulfide reductase inhibitors were designed in various chemical series to evaluate the impact of each inhibition mode on the propagation of the parasites. Against malaria parasites in cultures the most potent and specific effects were observed for redox- active agents acting as subversive substrates for both glutathione reductases of the Plasmodium-infected red blood cells. In their oxidized form, these redox-active compounds are reduced by NADPH-dependent flavoenzyme-catalyzed reactions in the cytosol of infected erythrocytes. In their reduced forms, these compounds can reduce molecular oxygen to reactive oxygen species, or reduce oxidants like methemoglobin, the major nutrient of the parasite, to indigestible hemoglobin. Furthermore, studies on a fluorinated suicide-substrate of the human glutathione reductase indicate that the glutathione reductase-catalyzed bioactivation of 3-benzylnaphthoquinones to the corresponding reduced 3-benzoyl metabolites is essential for the observed antimalarial activity. In conclusion, the antimalarial lead naphthoquinones are suggested to perturb the major redox equilibria of the targeted cells. These effects result in developmental arrest of the parasite and contribute to the removal of the parasitized erythrocytes by macrophages.
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Belorgey Didier, Antoine Lanfranchi Don and Davioud-Charvet Elisabeth, 1,4-Naphthoquinones and Other NADPH-Dependent Glutathione Reductase- Catalyzed Redox Cyclers as Antimalarial Agents, Current Pharmaceutical Design 2013; 19 (14) . https://dx.doi.org/10.2174/1381612811319140003
DOI https://dx.doi.org/10.2174/1381612811319140003 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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