CONICET | Buscador de Institutos y Recursos Humanos

Trypanosoma cruzi, the causative agent of Chagas disease, has a metabolism largely based on the consumption 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 on transport processes since the parasite is unable to de novo synthesize them. In this work, computational simulations combined with in vitro assays were used to identify new inhibitors of the proline and polyamines transporters that also present trypanocidal activity. Crystal violet used to be applied in blood banks as a trypanocidal agent (discontinued due to its high toxicity) and it was selected for the similarity-based virtual screening as a starting point to find new inhibitors of the proline permease since its mechanism of action involves the inhibition of proline transport. To search for polyamine transport inhibitors, the reference molecule was a conjugate of a polyamine with anthracene, an experimental oncological drug. Using these compounds, a similarity screening was performed on structures databases of approved drugs. Three drugs were found to be in vitro inhibitors of the proline transporter and also had trypanocidal activity with IC50s between 1 and 13 µM in trypomastigote and amastigote forms. Other three drugs had similar effects over the 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 drug repurposing or drug repositioning. One of the main advantages of this experimental approach is that reduces the time and the economic cost of implementation of new therapeutic alternatives, which is especially important in neglected diseases, like Chagas.