TY - JOUR
T1 - Combining bioinformatics, cheminformatics, functional genomics and whole organism approaches for identifying epigenetic drug targets in Schistosoma mansoni
AU - Padalino, Gilda
AU - Ferla, Salvatore
AU - Brancale, Andrea
AU - Chalmers, Iain
AU - Hoffmann, Karl
N1 - Funding Information:
We acknowledge all members of the Hoffmann laboratory for assisting in the maintenance of the schistosome lifecycle. Some B. glabrata snails used in this study were provided by the NIAID Schistosomiasis Resource Center of the Biomedical Research Institute (Rockville, MD, USA) through NIH-NIAID Contract HHSN272201000005I for distribution through BEI Resources. This work was jointly supported by the Welsh Government Life Sciences Research Network Wales as part of Ser Cymru programme (grants: NRNS3Apr004, NRNPGSep14001 and NRNPGSep14008) and the Wellcome Trust (grant 107475/Z/15/Z).
Funding Information:
We acknowledge all members of the Hoffmann laboratory for assisting in the maintenance of the schistosome lifecycle. Some B. glabrata snails used in this study were provided by the NIAID Schistosomiasis Resource Center of the Biomedical Research Institute (Rockville, MD, USA) through NIH-NIAID Contract HHSN272201000005I for distribution through BEI Resources. This work was jointly supported by the Welsh Government Life Sciences Research Network Wales as part of Ser Cymru programme (grants: NRNS3Apr004 , NRNPGSep14001 and NRNPGSep14008 ) and the Wellcome Trust (grant 107475/Z/15/Z ).
Publisher Copyright:
© 2018 The Authors
PY - 2018/12/31
Y1 - 2018/12/31
N2 - 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.
AB - 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.
KW - anthelmintic drug discovery
KW - neglected tropical diseases
KW - Schistosoma mansoni
KW - epigenetics
KW - lysine specific demethylase
KW - Neglected tropical diseases
KW - Epigenetics
KW - Anthelmintic drug discovery
KW - Lysine specific demethylase
KW - Humans
KW - Computational Biology/methods
KW - Epigenesis, Genetic/drug effects
KW - Drug Delivery Systems
KW - RNA Interference
KW - Praziquantel/pharmacology
KW - Schistosomiasis mansoni/drug therapy
KW - Histone Methyltransferases/drug effects
KW - Genomics/methods
KW - Drug Discovery
KW - Hep G2 Cells
KW - Animals
KW - Histone Demethylases/drug effects
KW - Schistosoma mansoni/drug effects
KW - Mice
KW - Molecular Docking Simulation
KW - Anthelmintics/therapeutic use
UR - http://www.scopus.com/inward/record.url?scp=85056324258&partnerID=8YFLogxK
U2 - 10.1016/j.ijpddr.2018.10.005
DO - 10.1016/j.ijpddr.2018.10.005
M3 - Article
C2 - 30455056
SN - 2211-3207
VL - 8
SP - 559
EP - 570
JO - International Journal for Parasitology: Drugs and Drug Resistance
JF - International Journal for Parasitology: Drugs and Drug Resistance
IS - 3
ER -