Abstract
BackgroundNew classes of anti-malarial drugs are needed to control the alarming Plasmodium falciparum resistance toward current anti-malarial therapy. The ethnopharmacological approach allows the discovery of original chemical structures from the vegetable biodiversity. Previous studies led to the selection of a bisbenzylisoquinoline, called cepharanthine and isolated from a Cambodian plant: Stephania rotunda. Cepharanthine could exert a mechanism of action different from commonly used drugs. Potential plasmodial targets are reported here.MethodsTo study the mechanism of action of cepharanthine, a combined approach using phenotypic and transcriptomic techniques was undertaken.ResultsCepharanthine blocked P. falciparum development in ring stage. On a culture of synchronized ring stage, the comparisons of expression profiles showed that the samples treated with 5 μM of cepharanthine (IC90) were significantly closer to the initial controls than to the final ones. After a two-way ANOVA (p-value < 0.05) on the microarray results, 1,141 probes among 9,722 presented a significant differential expression.A gene ontology analysis showed that the Maurer’s clefts seem particularly down-regulated by cepharanthine. The analysis of metabolic pathways showed an impact on cell-cell interactions (cytoadherence and rosetting), glycolysis and isoprenoid pathways. Organellar functions, more particularly constituted by apicoplast and mitochondrion, are targeted too.ConclusionThe blockage at the ring stage by cepharanthine is described for the first time. Transcriptomic approach confirmed that cepharanthine might have a potential innovative antiplasmodial mechanism of action. Thus, cepharanthine might play an ongoing role in the progress on anti-malarial drug discovery efforts.Electronic supplementary materialThe online version of this article (doi:10.1186/1475-2875-13-327) contains supplementary material, which is available to authorized users.
Highlights
New classes of anti-malarial drugs are needed to control the alarming Plasmodium falciparum resistance toward current anti-malarial therapy
Parasites were incubated with cepharanthine at the concentration corresponding to the Concentration inhibiting 50% of parasitic growth (IC50) level
Drug sensitivity assay The IC50 values of cepharanthine, CQ and MQ were respectively between 927 and 3,059 nM, 21.2 and 738 nM, 14.3 and 67.0 nM depending on the P. falciparum strain used (Table 1)
Summary
New classes of anti-malarial drugs are needed to control the alarming Plasmodium falciparum resistance toward current anti-malarial therapy. In the context of the widespread and increasing occurrence of Plasmodium falciparum resistance against current anti-malarial therapy, new anti-malarial compounds are urgently needed to treat this major endemic disease. In this perspective, it is interesting to note that for many synthetic anti-malarial drugs, P. falciparum-resistant isolates were observed one to 12 years after the first use, whereas it was longer for the natural compounds [2]. Structurally different from the available antimalarial drugs and targeting innovative and independent metabolism pathways, are needed to prevent the apparition of resistance and to improve care. Drawing from the rich plant biodiversity, new chemical structures may be helpful in the fight against malaria [7]
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