title: A physico-biochemical study on potential redox-cyclers as antimalarial and anti-schistosomal drugs.
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 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.
authors.affiliation: Laboratoire de Chimie Bioorganique et Medicinale, European School of Chemistry, Polymers and Materials, University of Strasbourg and Centre National de la Recherche Scientifique, UMR 7509, 25, rue Becquerel, F-67087 Strasbourg, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Johann
authors.forename: Don Antoine
authors.initials: DA
authors.lastname: Lanfranchi
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Davioud-Charvet
authors.forename: Mourad
authors.initials: M
authors.lastname: Elhabiri
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D006801:Humans; D008288:Malaria / Q000188:drug therapy*; D010084:Oxidation-Reduction; D010965:Plasmodium malariae / Q000187:drug effects* / Q000378:metabolism*; D012547:Schistosoma / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism*; D012552:Schistosomiasis / Q000188:drug therapy*; D012556:Schistosomicides / Q000627:therapeutic use*
chemical_list: D000962:Antimalarials; D012556:Schistosomicides