Show simple item record Padalino, Gilda Ferla, Salvatore Brancale, Andrea Chalmers, Iain Hoffmann, Karl 2018-11-15T19:33:05Z 2018-11-15T19:33:05Z 2018-12-01
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 , vol. 8 , no. 3 , pp. 559-570 . en
dc.identifier.issn 2211-3207
dc.identifier.other PURE: 28367450
dc.identifier.other PURE UUID: 4edfec5e-1e7a-4e34-9ef9-c8cfa01bcf91
dc.identifier.other Scopus: 85056324258
dc.identifier.other ORCID: /0000-0002-3932-5502/work/61775839
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.format.extent 12 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.contributor.institution Other Projects en
dc.contributor.institution Department of Biological, Environmental and Rural Sciences en
dc.description.status Peer reviewed en

Files in this item

Aside from theses and in the absence of a specific licence document on an item page, all works in Cadair are accessible under the CC BY-NC-ND Licence. AU theses and dissertations held on Cadair are made available for the purposes of private study and non-commercial research and brief extracts may be reproduced under fair dealing for the purpose of criticism or review. If you have any queries in relation to the re-use of material on Cadair, contact

This item appears in the following Collection(s)

Show simple item record

Search Cadair

Advanced Search