Computational repositioning of bioactive compounds from large chemogenomic screens: identification of conserved druggable modules between yeasts and trypanosomes

DIDIER GARNHAM M; URAN LANDABURU L; AGÜERO F

Mendoza

Congreso; XI Congreso de la Sociedad Argentina de Protozoologia (SAP); 2022

Sociedad Argentina de Protozoologia y Enfermedades Parasitarias

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, thus providing a rich source of pharmacogenomic associations between drugs and genes (?druggable modules?). In contrast, in trypanosomes, pharmacogenomic associations are scarce; hence yeast chemogenomic screens may serve as good starting points to guide repurposing opportunities for Chagas Disease. 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. From 5 published assays, we obtained 271.955 gene-drug interactions, with a set of 5.811 unique genes and 2.935 unique drugs. Further filters were applied to each set using this pipeline, to find conserved druggable modules between yeasts and Trypanosoma cruzi. For drugs, filters were applied to retain compounds that were drug-like, novel, commercially available, and with low potential promiscuity. For genes, we selected those that displayed significant fitness phenotypes when knocked down (in Trypanosoma brucei, through an orthology mapping between T. cruzi and the whole-genome RNAi essentiality assays described in Alsford et al, 2011). After standardization and filtering we obtained a library of 174 compounds, associated with 66 candidate protein targets in T. cruzi. We purchased 22 of those compounds and assessed their antiparasitic activity in vitro to validate the strategy. Results of these assays will be presented and discussed at the meeting. With this approach we expect to find novel drug candidates to treat Chagas disease.