ArticlePLoS neglected tropical diseases2015
Application of RNAi to Genomic Drug Target Validation in Schistosomes.
Article in PLoS neglected tropical diseases, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed, 50 citations in OpenAlex.
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- A global phosphoproteomics analysis of adult Fasciola gigantica by LC-MS/MS.Parasitology research · 2022Article
- De novo transcriptome assembly and identification of G-Protein-Coupled-Receptors (GPCRs) in two species of monogenean parasites of fish.Parasite (Paris, France) · 2022Article
- Discovery and Optimization of Selective Inhibitors of Meprin α (Part I).Pharmaceuticals (Basel, Switzerland) · 2021Article
- Large-scale RNAi screening uncovers therapeutic targets in the parasiteScience (New York, N.Y.) · 2020Article
- Biological and morphological consequences of dsRNA-induced suppression of tetraspanin mRNA in developmental stages of Echinococcus granulosus.Parasites & vectors · 2020Article
- Targeting Kinases inFrontiers in veterinary science · 2020Article
- Article
- Reference gene analysis and its use for kinase expression profiling in Fasciola hepatica.Scientific reports · 2019Article
- Calmodulin-specific small interfering RNA induces consistent expression suppression and morphological changes in Echinococcus granulosus.Scientific reports · 2019Article
- A novel cell-free method to culture Schistosoma mansoni from cercariae to juvenile worm stages for in vitro drug testing.PLoS neglected tropical diseases · 2019Article
- Interactive online application for the prediction, ranking and prioritisation of drug targets in Schistosoma haematobium.Parasites & vectors · 2018Article
- Clearance of schistosome parasites by resistant genotypes at a single genomic region in Biomphalaria glabrata snails involves cellular components of the hemolymph.International journal for parasitology · 2018Article
- Schistosome infectivity in the snail, Biomphalaria glabrata, is partially dependent on the expression of Grctm6, a Guadeloupe Resistance Complex protein.PLoS neglected tropical diseases · 2017Article
- Molecular characterization of host-parasite cell signalling in Schistosoma mansoni during early development.Scientific reports · 2016Article
- Calmodulin disruption impacts growth and motility in juvenile liver fluke.Parasites & vectors · 2016Article
- Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni.PLoS neglected tropical diseases · 2016Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Concerns over the possibility of resistance developing to praziquantel (PZQ), has stimulated efforts to develop new drugs for schistosomiasis. In addition to the development of improved whole organism screens, the success of RNA interference (RNAi) in schistosomes offers great promise for the identification of potential drug targets to initiate drug discovery. In this study we set out to contribute to RNAi based validation of putative drug targets. Initially a list of 24 target candidates was compiled based on the identification of putative essential genes in schistosomes orthologous of C. elegans essential genes. Knockdown of Calmodulin (Smp_026560.2) (Sm-Calm), that topped this list, produced a phenotype characterised by waves of contraction in adult worms but no phenotype in schistosomula. Knockdown of the atypical Protein Kinase C (Smp_096310) (Sm-aPKC) resulted in loss of viability in both schistosomula and adults and led us to focus our attention on other kinase genes that were identified in the above list and through whole organism screening of known kinase inhibitor sets followed by chemogenomic evaluation. RNAi knockdown of these kinase genes failed to affect adult worm viability but, like Sm-aPKC, knockdown of Polo-like kinase 1, Sm-PLK1 (Smp_009600) and p38-MAPK, Sm-MAPK p38 (Smp_133020) resulted in an increased mortality of schistosomula after 2-3 weeks, an effect more marked in the presence of human red blood cells (hRBC). For Sm-PLK-1 the same effects were seen with the specific inhibitor, BI2536, which also affected viable egg production in adult worms. For Sm-PLK-1 and Sm-aPKC the in vitro effects were reflected in lower recoveries in vivo. We conclude that the use of RNAi combined with culture with hRBC is a reliable method for evaluating genes important for larval development. However, in view of the slow manifestation of the effects of Sm-aPKC knockdown in adults and the lack of effects of Sm-PLK-1 and Sm-MAPK p38 on adult viability, these kinases may not represent suitable drug targets.
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