Discovery and Characterization of Novel Anti-schistosomal Properties of the Anti-anginal Drug, Perhexiline and Its Impact on Schistosoma mansoni Male and Female Reproductive Systems

摘要: Background Schistosomiasis, one of the world’s greatest human neglected tropical diseases, is caused by parasitic trematodes genus Schistosoma. A unique feature schistosome biology that induction sexual maturation as well maintenance differentiation status female reproductive organs and egg production, necessary for both disease transmission pathogenesis, are strictly dependent on male. The treatment most control initiatives schistosomiasis rely today long-term application a single drug, praziquantel (PZQ), mostly campaigns mass drug administration. PZQ, while very active adult parasites, has much lower activity against juvenile worms. Monotherapy also favors selection resistance and, therefore, new drugs urgently needed. Methods Findings Following screening small compound library with an ATP-based luminescent assay Schistosoma mansoni schistosomula, we here report identification characterization novel antischistosomal properties anti-anginal perhexiline maleate (PHX). By phenotypic worm survival assays confocal microscopy studies show PHX, in vitro, marked lethal effect all S. parasite life stages (newly transformed worms) definitive host. We further demonstrate sub-lethal doses PHX significantly impair production lipid depletion within vitellarium Moreover, highlighted tegumental damage male worms remarkable system alterations parasites. vivo study mansoni-patent mice showed notable variability burdens individual experiments, overall minimal schistosomicidal upon treatment. short half-life mice, together its high rodent plasma proteins binding could be cause modest efficacy murine model. Conclusions/Significance Overall, our data indicate represent promising starting point discovery programmes.