CONICET | Buscador de Institutos y Recursos Humanos

Polyamines are aliphatic polycations that participate in cell growth and differentiation. In T. cruzi the transport of polyamines is an essential process since it is unable to synthesize these compounds de novo. In a similar way, the amino acid proline is also involved in differentiation processes, cellular invasion and stress responses. T. cruzi polyamine and proline permeases were functionally characterized and studied as drug targets by our laboratory. Inhibitors of these permeases were identified by computational simulations combined with in vitro assays. In the case of the proline permease, for the similarity-based virtual screening, the compound crystal violet was selected as a starting point. Crystal violet was used in blood banks as a trypanocidal agent (discontinued due to its high toxicity) whose 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 using algorithms that compare molecule shapes and electrostatic potentials. Three drugs (loratadine, cyproheptadine and clofazimine) were found to be in vitro inhibitors of the proline transporter and also had trypanocidal activity with IC50 between 1 and 13 µM in trypomastigote and amastigote forms. Other three drugs (promazine, chlorpromazine and clomipramine) had similar effects over the polyamine transporter and the parasites with IC50 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 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.