Fueling open innovation for malaria transmission-blocking drugs: hundreds of molecules targeting early parasite mosquito stages

作者: Michael Delves , M. Jose Lafuente-Monasterio , Leanna Upton , Andrea Ruecker , Didier Leroy

DOI: 10.3389/FMICB.2019.02134

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摘要: Background: Despite recent successes at controlling malaria, progress has stalled with an estimated 219 million cases and 435,000 deaths in 2017 alone. Combined emerging resistance to front line antimalarial therapies Southeast Asia, there is urgent need for new treatment options novel approaches halt the spread of malaria. Plasmodium, parasite responsible malaria propagates through mosquito transmission. This imposes acute bottleneck on population transmission-blocking interventions exploiting this vulnerability are recognized as vital elimination. Methods: 13,533 small molecules known activity against Plasmodium falciparum asexual parasites were screened additional ex vivo berghei ookinete development assay. Active then counterscreened dose response HepG2 cells determine their activity/cytotoxicity window selected non-toxic representative fully profiled a range transmission infection assays. Furthermore, entire dataset was compared other published screens same P. gametocytes female gametogenesis. Results: 437 inhibited formation IC50 10-fold selectivity cells. grouped into 49 chemical clusters three or more molecules, 25 doublets 94 singletons. Six representing six major scaffolds confirmed male oocyst standard membrane feeding assay 1 µM. When screening data library assays gametogenesis, it established that each identified distinct, but partially overlapping subsets molecules. However, unique show Conclusions: The excellent high throughput efficiently identifying targeting early stage development. Currently no capable all

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