title: A comparative chemogenomics strategy to predict potential drug targets in the metazoan pathogen, Schistosoma mansoni.
abstract: 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.
authors.affiliation: Sandler Center for Basic Research in Parasitic Diseases, California Institute for Quantitative Biosciences, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Conor R
authors.initials: CR
authors.lastname: Caffrey
authors.forename: Andreas
authors.initials: A
authors.lastname: Rohwer
authors.forename: Frank
authors.initials: F
authors.lastname: Oellien
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Marhöfer
authors.forename: Simon
authors.initials: S
authors.lastname: Braschi
authors.forename: Guilherme
authors.initials: G
authors.lastname: Oliveira
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
authors.forename: Paul M
authors.initials: PM
authors.lastname: Selzer
mesh_terms: D000818:Animals; D055808:Drug Discovery; D017238:Genes, Helminth; D049751:Genome, Helminth; D023281:Genomics / Q000379:methods; D015801:Helminth Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012550:Schistosoma mansoni / Q000187:drug effects / Q000235:genetics*; D012555:Schistosomiasis mansoni / Q000469:parasitology; D012556:Schistosomicides / Q000494:pharmacology
chemical_list: D015801:Helminth Proteins; D012556:Schistosomicides