Schistosoma mansonilysine specific demethylase 1 (SmLSD1) is a druggable target involved in parasite survival, oviposition and stem cell proliferation
Authors: Padalino G. , Celatka C. A. , Rienhoff H. Y. , Kalin J. H. , Cole P. A. , Lassalle D. , Grunau C. , Chalmers I. W. , Brancale A. , Hoffmann K. F. 
Published: September 2020

Schistosomiasis is a chronically-debilitating neglected tropical disease (NTD) that predominantly affects people living in resource-poor communities of tropical and subtropical countries.Schistosoma mansoni, one of three species responsible for most human infections, undergoes strict developmental regulation of gene expression that is carefully controlled by both genetic- and epigenetic- processes. As inhibition ofS. mansoniepigenetic machinery components has been shown to impair key transitions throughout the parasite’s digenetic lifecycle, this knowledge is currently fuelling the search for new epi-drug - based anthelmintics.

In this study, the anti-schistosomal activity of 39 re-purposedHomo sapiensLysine Specific Demethylase 1 (HsLSD1) inhibitors was investigated on key life cycle stages associated with both definitive (schistosomula, juvenile worms, sexually-mature adults) and intermediate host (miracidia) infection. The most active compound (compound33; e.g. schistosomula phenotype EC50= 4.370 µM; adult worm motility EC50= 2.137 µM) was subsequently used to provide further insight into the critical role ofS. mansonilysine specific demethylase 1 (SmLSD1) in adult worm oviposition and stem cell proliferation. Here, compound33treatment of adult schistosomes led to significant defects in egg production, intra-egg vitellocyte/ovum packaging and gonadal/neoblast stem cell proliferation. A greater abundance of H3K4me2 marks accompanied these phenotypes and supported specific inhibition of SmLSD1 in adult schistosomes by compound33.In silicoscreening indicated that compound33likely inhibits SmLSD1 activity by covalently reacting with the FAD cofactor.

This work suggests that evaluation of HsLSD1 - targeting epi-drugs could have utility in the search for next-generation anti-schistosomals. The ability of compound33to inhibit parasite survival, oviposition, H3K4me2 demethylation and stem cell proliferation warrants further investigations of this compound and its epigenetic target. This data further highlights the importance of histone methylation inS. mansonilifecycle transitions.

Author summary

Affecting over 200 million people, schistosomiasis is a chronic disease caused by the parasitic wormSchistosoma mansoni. The frontline drug for schistosomiasis treatment is praziquantel. Owing to the concern surrounding praziquantel insensitivity or resistance developing, current research is directed towards the identification of novel drugs. We have focused our search for compounds that affect essential aspects of schistosome biology including parasite movement, fertility, cell proliferation and survival. Since all of these functions are potentially influenced by epigenetic regulation of gene expression, we investigated the activity of compounds that alter histone methylation status. In this report, we show thatS. mansoniLysine Specific Demethylase 1 (SmLSD1), a histone demethylase, is critical to miracidia-to-sporocyst transitioning, adult worm motility, egg production and parasite survival. Inhibition of SmLSD1 with compounds developed to inhibit the human paralog show promising potential as novel anti-schistosomal agents.