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.

Figure 1. In silico workflows to identify putative drug target proteins in S. mansoni based on sequence and phenotype comparisons.

A and B, representations of two independent workflows leading to a similar number of potential targets. C, the combination of workflows A and B generating a final number of 72 sequences (octagon) of which 63 were identical. Numbers of sequences used in each step are indicated within the respective circles. Depending on the intersection, the numbers within represent either sequence orthologs or S. mansoni proteins for which a deleterious phenotype is recorded in either Wormbase or Flybase. Blue, red and yellow circles display sequences from C. elegans (Ce), D. melanogaster (Dm), and S. mansoni (Sm), respectively. Details of the workflows are described in the text.