CONICET | Buscador de Institutos y Recursos Humanos

Trypanosoma cruzi, the causative agent of Chagas disease, has a metabolism largely based on theconsumption of glucose and amino acids. Among them, proline is also involved in differentiation processes,cellular invasion and stress responses. Polyamines are essential compounds to all living cells and in T.cruzi, besides their participation in cell growth and differentiation, its acquisition relies exclusively ontransport processes since the parasite is unable to de novo synthesize them. In this work, computationalsimulations combined with in vitro assays were used to identify new inhibitors of the proline and polyaminestransporters that also present trypanocidal activity. Crystal violet used to be applied in blood banks as atrypanocidal agent (discontinued due to its high toxicity) and it was selected for the similarity-based virtualscreening as a starting point to find new inhibitors of the proline permease since its mechanism of actioninvolves the inhibition of proline transport. To search for polyamine transport inhibitors, the referencemolecule was a conjugate of a polyamine with anthracene, an experimental oncological drug. Using thesecompounds, a similarity screening was performed on structures databases of approved drugs. Three drugswere found to be in vitro inhibitors of the proline transporter and also had trypanocidal activity with IC50sbetween 1 and 13 μM in trypomastigote and amastigote forms. Other three drugs had similar effects overthe polyamine transporter and the parasites with IC50s between 1 and 4 μM. The strategy herein applied,based on the screening of approved compounds used to treat other pathologies, is known as drugrepurposing or drug repositioning. One of the main advantages of this experimental approach is thatreduces the time and the economic cost of implementation of new therapeutic alternatives, which isespecially important in neglected diseases, like Chagas.

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