A comparative chemogenomics strategy to predict potential drug targets in the metazoan pathogen, Schistosoma mansoni.
Schistosomiasis is a prevalent and chronic helmintic disease in tropical regions. Treatment and control relies on chemotherapy with just one drug, praziquantel and this reliance is of concern should clinically relevant drug resistance emerge and spread. Therefore, to identify potential target protei...
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2009
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oai:doaj.org-article:6f89ee6c78bd429a904d5fb89455d6602021-11-25T06:17:26ZA comparative chemogenomics strategy to predict potential drug targets in the metazoan pathogen, Schistosoma mansoni.1932-620310.1371/journal.pone.0004413https://doaj.org/article/6f89ee6c78bd429a904d5fb89455d6602009-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19198654/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Schistosomiasis is a prevalent and chronic helmintic disease in tropical regions. Treatment and control relies on chemotherapy with just one drug, praziquantel and this reliance is of concern should clinically relevant drug resistance emerge and spread. Therefore, to identify potential target proteins for new avenues of drug discovery we have taken a comparative chemogenomics approach utilizing the putative proteome of Schistosoma mansoni compared to the proteomes of two model organisms, the nematode, Caenorhabditis elegans and the fruitfly, Drosophila melanogaster. Using the genome comparison software Genlight, two separate in silico workflows were implemented to derive a set of parasite proteins for which gene disruption of the orthologs in both the model organisms yielded deleterious phenotypes (e.g., lethal, impairment of motility), i.e., are essential genes/proteins. Of the 67 and 68 sequences generated for each workflow, 63 were identical in both sets, leading to a final set of 72 parasite proteins. All but one of these were expressed in the relevant developmental stages of the parasite infecting humans. Subsequent in depth manual curation of the combined workflow output revealed 57 candidate proteins. Scrutiny of these for 'druggable' protein homologs in the literature identified 35 S. mansoni sequences, 18 of which were homologous to proteins with 3D structures including co-crystallized ligands that will allow further structure-based drug design studies. The comparative chemogenomics strategy presented generates a tractable set of S. mansoni proteins for experimental validation as drug targets against this insidious human pathogen.Conor R CaffreyAndreas RohwerFrank OellienRichard J MarhöferSimon BraschiGuilherme OliveiraJames H McKerrowPaul M SelzerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 4, Iss 2, p e4413 (2009) |
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Medicine R Science Q |
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Medicine R Science Q Conor R Caffrey Andreas Rohwer Frank Oellien Richard J Marhöfer Simon Braschi Guilherme Oliveira James H McKerrow Paul M Selzer A comparative chemogenomics strategy to predict potential drug targets in the metazoan pathogen, Schistosoma mansoni. |
| description |
Schistosomiasis is a prevalent and chronic helmintic disease in tropical regions. Treatment and control relies on chemotherapy with just one drug, praziquantel and this reliance is of concern should clinically relevant drug resistance emerge and spread. Therefore, to identify potential target proteins for new avenues of drug discovery we have taken a comparative chemogenomics approach utilizing the putative proteome of Schistosoma mansoni compared to the proteomes of two model organisms, the nematode, Caenorhabditis elegans and the fruitfly, Drosophila melanogaster. Using the genome comparison software Genlight, two separate in silico workflows were implemented to derive a set of parasite proteins for which gene disruption of the orthologs in both the model organisms yielded deleterious phenotypes (e.g., lethal, impairment of motility), i.e., are essential genes/proteins. Of the 67 and 68 sequences generated for each workflow, 63 were identical in both sets, leading to a final set of 72 parasite proteins. All but one of these were expressed in the relevant developmental stages of the parasite infecting humans. Subsequent in depth manual curation of the combined workflow output revealed 57 candidate proteins. Scrutiny of these for 'druggable' protein homologs in the literature identified 35 S. mansoni sequences, 18 of which were homologous to proteins with 3D structures including co-crystallized ligands that will allow further structure-based drug design studies. The comparative chemogenomics strategy presented generates a tractable set of S. mansoni proteins for experimental validation as drug targets against this insidious human pathogen. |
| format |
article |
| author |
Conor R Caffrey Andreas Rohwer Frank Oellien Richard J Marhöfer Simon Braschi Guilherme Oliveira James H McKerrow Paul M Selzer |
| author_facet |
Conor R Caffrey Andreas Rohwer Frank Oellien Richard J Marhöfer Simon Braschi Guilherme Oliveira James H McKerrow Paul M Selzer |
| author_sort |
Conor R Caffrey |
| title |
A comparative chemogenomics strategy to predict potential drug targets in the metazoan pathogen, Schistosoma mansoni. |
| title_short |
A comparative chemogenomics strategy to predict potential drug targets in the metazoan pathogen, Schistosoma mansoni. |
| title_full |
A comparative chemogenomics strategy to predict potential drug targets in the metazoan pathogen, Schistosoma mansoni. |
| title_fullStr |
A comparative chemogenomics strategy to predict potential drug targets in the metazoan pathogen, Schistosoma mansoni. |
| title_full_unstemmed |
A comparative chemogenomics strategy to predict potential drug targets in the metazoan pathogen, Schistosoma mansoni. |
| title_sort |
comparative chemogenomics strategy to predict potential drug targets in the metazoan pathogen, schistosoma mansoni. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2009 |
| url |
https://doaj.org/article/6f89ee6c78bd429a904d5fb89455d660 |
| work_keys_str_mv |
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