Schistosomiasis, one of the world’s greatest human neglected tropical diseases, is caused by parasitic trematodes of the genus Schistosoma. A unique feature of schistosome biology is that the induction of sexual maturation as well as the maintenance of the differentiation status of female reproductive organs and egg production, necessary for both disease transmission and pathogenesis, are strictly dependent on the male. The treatment and most control initiatives of schistosomiasis rely today on the long-term application of a single drug, praziquantel (PZQ), mostly by campaigns of mass drug administration. PZQ, while very active on adult parasites, has much lower activity against juvenile worms. Monotherapy also favors the selection of drug resistance and, therefore, new drugs are urgently needed.
Following the screening of a small compound library with an ATP-based luminescent assay on Schistosoma mansoni schistosomula, we here report the identification and characterization of novel antischistosomal properties of the anti-anginal drug perhexiline maleate (PHX). By phenotypic worm survival assays and confocal microscopy studies we show that PHX, in vitro, has a marked lethal effect on all S. mansoni parasite life stages (newly transformed schistosomula, juvenile and adult worms) of the definitive host. We further demonstrate that sub-lethal doses of PHX significantly impair egg production and lipid depletion within the vitellarium of adult female worms. Moreover, we highlighted tegumental damage in adult male worms and remarkable reproductive system alterations in both female and male adult parasites. The in vivo study in S. mansoni-patent mice showed a notable variability of worm burdens in the individual experiments, with an overall minimal schistosomicidal effect upon PHX treatment. The short PHX half-life in mice, together with its very high rodent plasma proteins binding could be the cause of the modest efficacy of PHX in the schistosomiasis murine model.
Schistosomiasis is one of the 17 neglected tropical diseases prioritized by the World Health Organization. It affects hundreds of millions of people in developing countries in the poorest tropical and subtropical regions of the world. Today, essentially a single drug, praziquantel (PZQ), is available to treat this parasitic disease. PZQ incomplete efficacy across all stages of the Schistosoma mansoni life cycle in the definitive host and the potential risk of drug resistance prompted us to search for novel schistosomicidal molecules. We screened a compound collection library using the larval stage of the parasite and discovered novel anti-schistosomal properties of perhexiline maleate (PHX). Overall, our study demonstrated that the anti-anginal drug PHX, still used in some countries, is active in vitro against parasite life stages poorly sensitive to PZQ. In addition, we showed that PHX impairs egg production in mature worm couples in vitro and damages the female and male reproductive systems and the male worm tegument. PHX could therefore represent a promising starting point for novel schistosomicidal drug discovery programmes.