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dc.contributor.author Padalino, Gilda
dc.contributor.author Ferla, Salvatore
dc.contributor.author Brancale, Andrea
dc.contributor.author Chalmers, Iain
dc.contributor.author Hoffmann, Karl
dc.date.accessioned 2018-11-15T19:33:05Z
dc.date.available 2018-11-15T19:33:05Z
dc.date.issued 2018-11-13
dc.identifier.citation Padalino , G , Ferla , S , Brancale , A , Chalmers , I & Hoffmann , K 2018 , ' Combining bioinformatics, cheminformatics, functional genomics and whole organism approaches for identifying epigenetic drug targets in Schistosoma mansoni ' International Journal for Parasitology: Drugs and Drug Resistance . DOI: 10.1016/j.ijpddr.2018.10.005 en
dc.identifier.issn 2211-3207
dc.identifier.other PURE: 28367450
dc.identifier.other PURE UUID: 4edfec5e-1e7a-4e34-9ef9-c8cfa01bcf91
dc.identifier.other handle.net: http://hdl.handle.net/2160/4edfec5e-1e7a-4e34-9ef9-c8cfa01bcf91
dc.identifier.uri http://hdl.handle.net/2160/47108
dc.description.abstract Schistosomiasis endangers the lives of greater than 200 million people every year and is predominantly controlled by a single class chemotherapy, praziquantel (PZQ). Development of PZQ replacement (to combat the threat of PZQ insensitivity/resistance arising) or combinatorial (to facilitate the killing of PZQ-insensitive juvenile schistosomes) chemotherapies would help sustain this control strategy into the future. Here, we re-categorise two families of druggable epigenetic targets in Schistosoma mansoni, the histone methyltransferases (HMTs) and the histone demethylases (HDMs). Amongst these, a S. mansoni Lysine Specific Demethylase 1 (SmLSD1, Smp_150560) homolog was selected for further analyses. Homology modelling of SmLSD1 and in silico docking of greater than four thousand putative inhibitors identified seven (L1 – L7) showing more favourable binding to the target pocket of SmLSD1 vs Homo sapiens HsLSD1; six of these seven (L1 – L6) plus three structural analogues of L7 (L8 – L10) were subsequently screened against schistosomula using the Roboworm anthelmintic discovery platform. The most active compounds (L10 - pirarubicin > L8 – danunorubicin hydrochloride) were subsequently tested against juvenile (3 wk old) and mature (7 wk old) schistosome stages and found to impede motility, suppress egg production and affect tegumental surfaces. When compared to a surrogate human cell line (HepG2), a moderate window of selectivity was observed for the most active compound L10 (selectivity indices - 11 for schistosomula, 9 for juveniles, 1.5 for adults). Finally, RNA interference of SmLSD1 recapitulated the egg-laying defect of schistosomes co-cultivated in the presence of L10 and L8. These preliminary results suggest that SmLSD1 represents an attractive new target for schistosomiasis; identification of more potent and selective SmLSD1 compounds, however, is essential. Nevertheless, the approaches described herein highlight an interdisciplinary strategy for selecting and screening novel/repositioned anti-schistosomals, which can be applied to any druggable (epigenetic) target encoded by the parasite's genome en
dc.language.iso eng
dc.relation.ispartof International Journal for Parasitology: Drugs and Drug Resistance en
dc.rights en
dc.subject anthelmintic drug discovery en
dc.subject neglected tropical diseases en
dc.subject Schistosoma mansoni en
dc.subject epigenetics en
dc.subject lysine specific demethylase en
dc.title Combining bioinformatics, cheminformatics, functional genomics and whole organism approaches for identifying epigenetic drug targets in Schistosoma mansoni en
dc.type /dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article en
dc.description.version authorsversion en
dc.identifier.doi https://doi.org/10.1016/j.ijpddr.2018.10.005
dc.contributor.institution Other Projects en
dc.contributor.institution Department of Biological, Environmental and Rural Sciences en
dc.description.status Peer reviewed en


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