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Antioxid Redox Signal. 2012 Aug 15;17(4):544-54. doi: 10.1089/ars.2011.4239. Epub 2012 Jan 18.

Interactions of the antimalarial drug methylene blue with methemoglobin and heme targets in Plasmodium falciparum: a physico-biochemical study.

Author information

1
Laboratoire de Chimie Bioorganique et Médicinale, European School of Chemistry, Polymers and Materials (ECPM), University of Strasbourg and Centre National de la Recherche Scientifique, Strasbourg, France.

Abstract

AIMS:

Resistance of Plasmodium falciparum to drugs has led to renewed interest of redox-active methylene blue (MB) for which no resistance has been reported so far. Moreover, MB displays unique interactions with glutathione reductase (GR). However, the mechanisms of action/interaction with potential targets of MB are yet to be elucidated. Our physico-biochemical study on MB and relevant hematin-containing targets was performed under quasi-physiological conditions.

RESULTS:

The water deprotonation of the Fe(III)protoporphyrin dimer, the major building block of β-hematin, was studied. At pH 6, the predominant dimer possesses water coordinated to both metals. Below pH 6, spontaneous precipitation of β-hematin occurred reminiscent of hemozoin biomineralization at pH 5.0-5.5 in the food vacuole of the malarial parasite. MB also forms dimers (K(Dim)=6800 M(-1)) and firmly binds to hematin in a 2:1 hematin:MB sandwich complex (K(D)=3.16 μM). MB bioactivation catalyzed by GR induces efficient methemoglobin(Fe(III)) [metHb(Fe(III))] reduction to hemoglobin(Fe(II)). The reduction rate, mediated by leucomethylene blue (LMB), was determined (k(metHb)(red)=991 M(-1)·s(-1)) in an assay coupled to the GR/reduced form of nicotinamide adenine dinucleotide phosphate system.

INNOVATION AND CONCLUSION:

Our work provides new insights into the understanding of (i) how MB interacts with hematin-containing targets, (ii) other relevant MB properties in corroboration with the distribution of the three major LMB species as a function of pH, and (iii) how this redox-active cycler induces efficient catalytic reduction of metHb(Fe(III)) to hemoglobin(Fe(II)) mediated by oxidoreductases. These physico-biochemical parameters of MB open promising perspectives for the interpretation of the pharmacology and pathophysiology of malaria and possibly new routes for antimalarial drug development.

PMID:
22256987
DOI:
10.1089/ars.2011.4239
[Indexed for MEDLINE]

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