Fiche publication
Date publication
janvier 2012
Journal
Current pharmaceutical design
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DAVIOUD-CHARVET Elisabeth
,
Dr ELHABIRI Mourad
Tous les auteurs :
Johann L, Lanfranchi DA, Davioud-Charvet E, Elhabiri M
Lien Pubmed
Résumé
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 K(D) 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.
Mots clés
Animals, Antimalarials, therapeutic use, Humans, Malaria, drug therapy, Oxidation-Reduction, Plasmodium malariae, drug effects, Schistosoma, drug effects, Schistosomiasis, drug therapy, Schistosomicides, therapeutic use
Référence
Curr. Pharm. Des.. 2012 ;18(24):3539-66
