Combining bioinformatics, cheminformatics, functional genomics and whole organism approaches for identifying epigenetic drug targets in Schistosoma mansoni
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 kill...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-12-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320718301337 |
| _version_ | 1811284193439645696 |
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| author | Gilda Padalino Salvatore Ferla Andrea Brancale Iain W. Chalmers Karl F. Hoffmann |
| author_facet | Gilda Padalino Salvatore Ferla Andrea Brancale Iain W. Chalmers Karl F. Hoffmann |
| author_sort | Gilda Padalino |
| collection | DOAJ |
| description | 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. Keywords: Anthelmintic drug discovery, Neglected tropical diseases, Schistosoma mansoni, Epigenetics, Lysine specific demethylase |
| first_indexed | 2024-04-13T02:24:54Z |
| format | Article |
| id | doaj.art-c2d48592aaed42c3a4575dd70e76d802 |
| institution | Directory Open Access Journal |
| issn | 2211-3207 |
| language | English |
| last_indexed | 2024-04-13T02:24:54Z |
| publishDate | 2018-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj.art-c2d48592aaed42c3a4575dd70e76d8022022-12-22T03:06:48ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072018-12-0183559570Combining bioinformatics, cheminformatics, functional genomics and whole organism approaches for identifying epigenetic drug targets in Schistosoma mansoniGilda Padalino0Salvatore Ferla1Andrea Brancale2Iain W. Chalmers3Karl F. Hoffmann4The Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, SY23 3DA, Wales, UKSchool of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF10 3NB, United KingdomSchool of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF10 3NB, United KingdomThe Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, SY23 3DA, Wales, UKThe Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, SY23 3DA, Wales, UK; Corresponding author.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. Keywords: Anthelmintic drug discovery, Neglected tropical diseases, Schistosoma mansoni, Epigenetics, Lysine specific demethylasehttp://www.sciencedirect.com/science/article/pii/S2211320718301337 |
| spellingShingle | Gilda Padalino Salvatore Ferla Andrea Brancale Iain W. Chalmers Karl F. Hoffmann 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 |
| title | Combining bioinformatics, cheminformatics, functional genomics and whole organism approaches for identifying epigenetic drug targets in Schistosoma mansoni |
| title_full | Combining bioinformatics, cheminformatics, functional genomics and whole organism approaches for identifying epigenetic drug targets in Schistosoma mansoni |
| title_fullStr | Combining bioinformatics, cheminformatics, functional genomics and whole organism approaches for identifying epigenetic drug targets in Schistosoma mansoni |
| title_full_unstemmed | Combining bioinformatics, cheminformatics, functional genomics and whole organism approaches for identifying epigenetic drug targets in Schistosoma mansoni |
| title_short | Combining bioinformatics, cheminformatics, functional genomics and whole organism approaches for identifying epigenetic drug targets in Schistosoma mansoni |
| title_sort | combining bioinformatics cheminformatics functional genomics and whole organism approaches for identifying epigenetic drug targets in schistosoma mansoni |
| url | http://www.sciencedirect.com/science/article/pii/S2211320718301337 |
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