Abstract
The role of redox enzymes in establishing a microenvironment for parasite development is well characterized. Mimicking human glucose-6-phosphate dehydrogenase and glutathione reductase (GR) deficiencies by redox-cycling compounds thus represents a challenge to the design of new preclinical antiparasitic drug candidates. Schistosomes and malarial parasites feed on hemoglobin. Heme, the toxic prosthetic group of the protein, is not digested and represents a challenge to the redox metabolism of the parasites. Here, we report on old and new redox-cycling compounds – whose antiparasitic activities are related to their interference with (met)hemoglobin degradation and hematin crystallization. Three key-assays allowed probing and differentiating the mechanisms of drug actions. Inhibition of β-hematin was first compared to the heme binding as a possible mode of action. All tested ligands interact with the hematin π-π dimer with KD similar to those measured for the major antiparasitic drugs. No correlation between a high affinity for hematin and the capacity to prevent β-hematin formation was however deduced. Inhibition of β-hematin formation is consequently not the result of a single process but results from redox processes following electron transfers from the drugs to iron(III)-containing targets. The third experiment highlighted that several redox-active compounds (in their reduced forms) are able to efficiently reduce methemoglobin to hemoglobin in a GR/NADPH-coupled assay. A correlation between methemoglobin reduction and inhibition of β-hematin was shown, demonstrating that both processes are closely related. The ability of our redox-cyclers to trigger methemoglobin reduction therefore constitutes a critical step to understand the mechanism of action of our drug candidates.
Keywords: hematin, β-hematin, antimalarial, antischistosomal, naphthoquinone, xanthone, NADPH-dependent disulfide reductase, redoxcycler, glutathione reductase (GR), hemoglobin
Current Pharmaceutical Design
Title:A Physico-Biochemical Study on Potential Redox-Cyclers as Antimalarial and Antischistosomal Drugs
Volume: 18 Issue: 24
Author(s): Laure Johann, Don Antoine Lanfranchi, Elisabeth Davioud-Charvet and Mourad Elhabiri
Affiliation:
Keywords: hematin, β-hematin, antimalarial, antischistosomal, naphthoquinone, xanthone, NADPH-dependent disulfide reductase, redoxcycler, glutathione reductase (GR), hemoglobin
Abstract: The role of redox enzymes in establishing a microenvironment for parasite development is well characterized. Mimicking human glucose-6-phosphate dehydrogenase and glutathione reductase (GR) deficiencies by redox-cycling compounds thus represents a challenge to the design of new preclinical antiparasitic drug candidates. Schistosomes and malarial parasites feed on hemoglobin. Heme, the toxic prosthetic group of the protein, is not digested and represents a challenge to the redox metabolism of the parasites. Here, we report on old and new redox-cycling compounds – whose antiparasitic activities are related to their interference with (met)hemoglobin degradation and hematin crystallization. Three key-assays allowed probing and differentiating the mechanisms of drug actions. Inhibition of β-hematin was first compared to the heme binding as a possible mode of action. All tested ligands interact with the hematin π-π dimer with KD similar to those measured for the major antiparasitic drugs. No correlation between a high affinity for hematin and the capacity to prevent β-hematin formation was however deduced. Inhibition of β-hematin formation is consequently not the result of a single process but results from redox processes following electron transfers from the drugs to iron(III)-containing targets. The third experiment highlighted that several redox-active compounds (in their reduced forms) are able to efficiently reduce methemoglobin to hemoglobin in a GR/NADPH-coupled assay. A correlation between methemoglobin reduction and inhibition of β-hematin was shown, demonstrating that both processes are closely related. The ability of our redox-cyclers to trigger methemoglobin reduction therefore constitutes a critical step to understand the mechanism of action of our drug candidates.
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Johann Laure, Antoine Lanfranchi Don, Davioud-Charvet Elisabeth and Elhabiri Mourad, A Physico-Biochemical Study on Potential Redox-Cyclers as Antimalarial and Antischistosomal Drugs, Current Pharmaceutical Design 2012; 18 (24) . https://dx.doi.org/10.2174/138161212801327284
DOI https://dx.doi.org/10.2174/138161212801327284 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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