A drug-target prioritization strategy using the TDR Targets database leads to novel trypanocidal compounds with known active functional groups.

LANDABURU, LU; TEKIEL V; AGUERO, F

Mendoza

Congreso; XI Congreso Sociedad Argentina de Protozoología.; 2022

SAP

COP-014A drug-target prioritization strategy using the TDR Targets database leads to novel trypanocidal compounds with known active functional groups.Urán Landaburu L, Tekiel V, Agüero FInstituto de Investigaciones Biotecnológicas (IIBIO), UNSAM-CONICET, Gral. San Martín, Argentina.ResumenThe drug repurposing approach to drug discovery for neglected diseases has shown to be effective to find potential therapeutic agents. For Chagas disease, in particular, with some of these agents even making it to clinical trials. We have shown that a programmatic approach for drug repurposing, using intensive chemogenic data integration strategies, can recall known bioactive compounds and druggable targets for a selected pathogen species, and can also recommend novel drug-target pairs for further experimental validation (Berenstein et al, 2016).In this work, we used the TDR Targets database (Landaburu et al, 2020) for target prioritization and drug recommendation, followed by a filtering pipeline addressing compound novelty, commercial availability and functional groups. As a result we obtained 18 compound libraries, each one collecting compounds with a different known active pharmacophore. In this work two libraries were selected for manual curation and further analysis: one library containing 28 piperazines, and another one containing 15 nitro-compounds). Out of a total of 43 compounds, 22 were acquired for experimental validation.Trypanocidal activity of these compounds was determined in-vitro against T. cruzi amastigotes growing in Vero cells, using Tulahuen parasites expressing a bacterial LacZ beta-galactosidase gene (Buckner 1996), incubating cultures with drug-supplemented (20 μM) RPMI media over 96 hs, and measuring ꞵ-gal activity as a proxy for parasite growth. Compound cytotoxicity was assessed in uninfected Vero cells by resazurin assay with similar drug concentrations.From this primary screening, 5 compounds displayed promising results, with good trypanocidal activity, and low/no cytotoxicity. An additional set of 4 compounds killed both host cells and parasites and thus should be assayed in lower concentrations to determine selectivity. All 9 compounds will be investigated further.