Abstract
BackgroundPlasmodium falciparum gametocytes, specifically mature stages, are the only stage in man transmissible to the mosquito vector responsible for malaria transmission. Anti-malarial drugs capable of killing these forms are considered essential for the eradication of malaria. The comprehensive profiling of in vitro activity of anti-malarial compounds against both early (I-III) and late (IV-V) stage P. falciparum gametocytes, along with the high throughput screening (HTS) outcomes from the MMV malaria box are described.MethodTwo anti-gametocyte HTS assays based on confocal fluorescence microscopy, utilizing both a gametocyte specific protein (pfs16-Luc-GFP) and a viability marker (MitoTracker Red CM-H2XRos) (MTR), were used for the measurement of anti-gametocytocidal activity. This combination provided a direct observation of gametocyte number per assay well, whilst defining the viability of each gametocyte imaged.ResultsIC50 values were obtained for 36 current anti-malarial compounds for activities against asexual, early and late stage gametocytes. The MMV malaria box was screened and actives progressed for IC50 evaluation. Seven % of the “drug-like” and 21% of the “probe-like” compounds from the MMV malaria box demonstrated equivalent activity against both asexual and late stage gametocytes.ConclusionsThe assays described were shown to selectively identify compounds with gametocytocidal activity and have been demonstrated suitable for HTS with the capability of screening in the order of 20,000 compounds per screening campaign, two to three times per seven-day week.
Highlights
Plasmodium falciparum gametocytes, mature stages, are the only stage in man transmissible to the mosquito vector responsible for malaria transmission
IC50 values were obtained for 36 current anti-malarial compounds for activities against asexual, early and late stage gametocytes
The Medicines for Malaria Venture (MMV) malaria box was screened and actives progressed for IC50 evaluation
Summary
Plasmodium falciparum gametocytes, mature stages, are the only stage in man transmissible to the mosquito vector responsible for malaria transmission. Anti-malarial drugs capable of killing these forms are considered essential for the eradication of malaria. The comprehensive profiling of in vitro activity of anti-malarial compounds against both early (I-III) and late (IV-V) stage P. falciparum gametocytes, along with the high throughput screening (HTS) outcomes from the MMV malaria box are described. Malaria is a disease resulting from infection by the intracellular parasite Plasmodium. It remains the most significant parasitic disease in the tropics where it causes ~200 million clinical cases and is reported to claim up to 1.2 million lives each year [1]. Substantial efforts are being made to reduce the number of clinical manifestations and deaths attributed to malaria, and to the complete eradication of this disease. International aid for continued malaria control in endemic malaria regions declined considerably during the 1970’s and 1980’s, recent renewed international efforts into malaria control and research has resulted in promising advances in new control measures
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