Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Caffrey, Conor R., Rohwer, Andreas, Oellien, Frank, Marhöfer, Richard J., Braschi, Simon, Oliveira, Guilherme, McKerrow, James H., Selzer, Paul M.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2635471/
https://www.ncbi.nlm.nih.gov/pubmed/19198654
http://dx.doi.org/10.1371/journal.pone.0004413
_version_ 1782164183661412352
author Caffrey, Conor R.
Rohwer, Andreas
Oellien, Frank
Marhöfer, Richard J.
Braschi, Simon
Oliveira, Guilherme
McKerrow, James H.
Selzer, Paul M.
author_facet Caffrey, Conor R.
Rohwer, Andreas
Oellien, Frank
Marhöfer, Richard J.
Braschi, Simon
Oliveira, Guilherme
McKerrow, James H.
Selzer, Paul M.
author_sort Caffrey, Conor R.
collection PubMed
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 Text
id pubmed-2635471
institution National Center for Biotechnology Information
language English
publishDate 2009
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-26354712009-02-09 A Comparative Chemogenomics Strategy to Predict Potential Drug Targets in the Metazoan Pathogen, Schistosoma mansoni Caffrey, Conor R. Rohwer, Andreas Oellien, Frank Marhöfer, Richard J. Braschi, Simon Oliveira, Guilherme McKerrow, James H. Selzer, Paul M. PLoS One Research Article 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. Public Library of Science 2009-02-09 /pmc/articles/PMC2635471/ /pubmed/19198654 http://dx.doi.org/10.1371/journal.pone.0004413 Text en Caffrey et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Caffrey, Conor R.
Rohwer, Andreas
Oellien, Frank
Marhöfer, Richard J.
Braschi, Simon
Oliveira, Guilherme
McKerrow, James H.
Selzer, Paul M.
A Comparative Chemogenomics Strategy to Predict Potential Drug Targets in the Metazoan Pathogen, Schistosoma mansoni
title 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_short 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
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2635471/
https://www.ncbi.nlm.nih.gov/pubmed/19198654
http://dx.doi.org/10.1371/journal.pone.0004413
work_keys_str_mv AT caffreyconorr acomparativechemogenomicsstrategytopredictpotentialdrugtargetsinthemetazoanpathogenschistosomamansoni
AT rohwerandreas acomparativechemogenomicsstrategytopredictpotentialdrugtargetsinthemetazoanpathogenschistosomamansoni
AT oellienfrank acomparativechemogenomicsstrategytopredictpotentialdrugtargetsinthemetazoanpathogenschistosomamansoni
AT marhoferrichardj acomparativechemogenomicsstrategytopredictpotentialdrugtargetsinthemetazoanpathogenschistosomamansoni
AT braschisimon acomparativechemogenomicsstrategytopredictpotentialdrugtargetsinthemetazoanpathogenschistosomamansoni
AT oliveiraguilherme acomparativechemogenomicsstrategytopredictpotentialdrugtargetsinthemetazoanpathogenschistosomamansoni
AT mckerrowjamesh acomparativechemogenomicsstrategytopredictpotentialdrugtargetsinthemetazoanpathogenschistosomamansoni
AT selzerpaulm acomparativechemogenomicsstrategytopredictpotentialdrugtargetsinthemetazoanpathogenschistosomamansoni
AT caffreyconorr comparativechemogenomicsstrategytopredictpotentialdrugtargetsinthemetazoanpathogenschistosomamansoni
AT rohwerandreas comparativechemogenomicsstrategytopredictpotentialdrugtargetsinthemetazoanpathogenschistosomamansoni
AT oellienfrank comparativechemogenomicsstrategytopredictpotentialdrugtargetsinthemetazoanpathogenschistosomamansoni
AT marhoferrichardj comparativechemogenomicsstrategytopredictpotentialdrugtargetsinthemetazoanpathogenschistosomamansoni
AT braschisimon comparativechemogenomicsstrategytopredictpotentialdrugtargetsinthemetazoanpathogenschistosomamansoni
AT oliveiraguilherme comparativechemogenomicsstrategytopredictpotentialdrugtargetsinthemetazoanpathogenschistosomamansoni
AT mckerrowjamesh comparativechemogenomicsstrategytopredictpotentialdrugtargetsinthemetazoanpathogenschistosomamansoni
AT selzerpaulm comparativechemogenomicsstrategytopredictpotentialdrugtargetsinthemetazoanpathogenschistosomamansoni