Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malaria is caused by protozoan parasites and remains a major public health issue in subtropical areas. Plasmodione (3-[4-(trifluoromethyl)benzyl]-menadione) is a novel early lead compound displaying fast-acting antimalarial activity. Treatment with this redox active compound disrupts the redox balance of parasite-infected red blood cells. In vitro, the benzoyl analogue of plasmodione can act as a subversive substrate of the parasite flavoprotein NADPH-dependent glutathione reductase, initiating a redox cycling process producing ROS. Whether this is also true in vivo remains to be investigated. Here, we used the yeast model to investigate the mode of action of plasmodione and uncover enzymes and pathways involved in its activity. We showed that plasmodione is a potent inhibitor of yeast respiratory growth, that in drug-treated cells, the ROS-sensitive aconitase was impaired and that cells with a lower oxidative stress defence were highly sensitive to the drug, indicating that plasmodione may act via an oxidative stress. We found that the mitochondrial respiratory chain flavoprotein NADH-dehydrogenases play a key role in plasmodione activity. Plasmodione and metabolites act as substrates of these enzymes, the reaction resulting in ROS production. This in turn would damage ROS-sensitive enzymes leading to growth arrest. Our data further suggest that plasmodione is a pro-drug whose activity is mainly mediated by its benzhydrol and benzoyl metabolites. Our results in yeast are coherent with existing data obtained in vitro and in Plasmodium falciparum, and provide additional hypotheses that should be investigated in parasites.
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PMID:Investigating the mode of action of the redox-active antimalarial drug plasmodione using the yeast model. 3123 26

With the aim to clarify the mechanism(s) of action of nitroaromatic compounds against the malaria parasite Plasmodium falciparum, we examined the single-electron reduction by P. falciparum ferredoxin:NADP+ oxidoreductase (PfFNR) of a series of nitrofurans and nitrobenzenes (n = 23), and their ability to inhibit P. falciparum glutathione reductase (PfGR). The reactivity of nitroaromatics in PfFNR-catalyzed reactions increased with their single-electron reduction midpoint potential (E17). Nitroaromatic compounds acted as non- or uncompetitive inhibitors towards PfGR with respect to NADPH and glutathione substrates. Using multiparameter regression analysis, we found that the in vitro activity of these compounds against P. falciparum strain FcB1 increased with their E17 values, octanol/water distribution coefficients at pH 7.0 (log D), and their activity as PfGR inhibitors. Our data demonstrate that both factors, the ease of reductive activation and the inhibition of PfGR, are important in the antiplasmodial in vitro activity of nitroaromatics. To the best of our knowledge, this is the first quantitative demonstration of this kind of relationship. No correlation between antiplasmodial activity and ability to inhibit human erythrocyte GR was detected in tested nitroaromatics. Our data suggest that the efficacy of prooxidant antiparasitic agents may be achieved through their combined action, namely inhibition of antioxidant NADPH:disulfide reductases, and the rapid reduction by single-electron transferring dehydrogenases-electrontransferases.
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PMID:Antiplasmodial Activity of Nitroaromatic Compounds: Correlation with Their Reduction Potential and Inhibitory Action on Plasmodium falciparum Glutathione Reductase. 3183 50


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