IIBIO   27936
INSTITUTO DE INVESTIGACIONES BIOTECNOLOGICAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Computational repositioning of bioactive compounds from large chemogenomic screens: identification of conserved druggable modules between yeasts and trypanosomes
Autor/es:
LIONEL URÁN LANDABURU; MERCEDES DIDIER GARNHAM; FERNAN AGÜERO
Lugar:
Mar del Plata
Reunión:
Congreso; Reunión Anual de Sociedades Biocientíficas; 2019
Institución organizadora:
Sociedad Argentina de Protozoología
Resumen:
Detailed characterization of the cellular response to chemicals is fundamental to understand the mechanism of action of drugs. One strategy to do this is to analyze the growth capacity (fitness) of gene mutants exposed to different drugs. Recently, a number of genome‐wide fitness profiling assays were performed on Saccharomyces cerevisiae. These chemical-genomics screens were based on whole-genome collections of heterozygous and homozygous deletions and quantified the growth fitness of each strain in the presence of different chemicals. Now, several such chemogenomic datasets are available, providing a rich source of pharmacogenomic associations between drugs and genes (?druggable modules?). In contrast, in trypanosomes pharmacogenomic associations are scarce, hence these yeast chemogenomic screens may serve as good starting points to guide repurposing opportunities. The aim of this project is the curation and standardization of yeast-based chemogenomic assays from published studies, and the development of an orthology mapping pipeline. Using this pipeline to find conserved druggable modules between yeasts and T. cruzi, we obtained 93,758 gene-drug interactions, with a set of 3,005 unique genes and 2,430 unique drugs. Further filters were applied to each set. For drugs, filters were applied to retain compounds that are drug-like, novel, commercially available, and with low potential promiscuity; with a final iteration to maximize chemical diversity within the set. For genes, we selected those that have T. brucei orthologs with significant fitness phenotypes when knocked down (through an orthology mapping between T. cruzi genes and T. brucei whole-genome RNAi essentiality assays described in Alsford et al, 2011). After standardization and filtering we obtained a library of 50 compounds, associated with 78 candidate protein targets in T. cruzi.