Artemisinins are proposed to act in the malaria parasite cytosol by oxidizing dihydroflavin cofactors of redox-active flavoenzymes, and under aerobic conditions by inducing their autoxidation.
In this study, we used an allelic exchange strategy to engineer parasite lines carrying the S769N mutations in P. falciparum strain 3D7 and evaluated whether introduction of this mutation modulated parasite sensitivity to ART derivatives.
Artemisinins rapidly oxidize leucomethylene blue (LMB) to methylene blue (MB); they also oxidize dihydroflavins such as the reduced conjugates RFH2 of riboflavin (RF), and FADH2 of the cofactor flavin adenine dinucleotide (FAD), to the corresponding flavins.
The number of available and effective antimalarial drugs is quickly dwindling.
Nowadays, artemisinins are the mainstay of malaria treatment, but initial indications of resistance against clinically used derivatives are present.
Flavin adenine dinucleotide (FAD) is reduced by NADPH–E. coli flavin reductase (Fre) to FADH2 in aqueous buffer at pH 7.4 under argon.
In this review different models of artemisinins’ molecular action are briefly presented, focusing on recent advances, and the evidence of potential association between various gene polymorphisms and artemisinin resistance is comprehensively reviewed.
These findings support a recently published WHO guide for malaria treatment with artemisinin regimens, such as artemisinin-based combination therapies and injectable artesunate, to avoid neurotoxicity.
The antimalarial drug methylene blue (MB) affects the redox behaviour of parasite flavin-dependent disulfide reductases such as glutathione reductase (GR) that control oxidative stress in the malaria parasite.
This is the first demonstration that DHA affects human erythropoiesis in vitro, in a dose- and time-dependent manner; the target population seems to be the pro-erythroblast and basophilic erythroblast stage, suggesting that DHA toxicity is limited to primitive human erythropoiesis.