CONICET | Buscador de Institutos y Recursos Humanos

Trypanosoma cruzi, the etiological agent of Chagas disease, has a metabolism largely basedon the consumption of glucose and proline. Additionally, this amino acid is involved indifferentiation processes, cellular invasion and resistance to several stresses as oxidative,metabolic and osmotic. We have previously identified the proline permease TcAAAP069 in T.cruzi and we showed the effect of inhibition and/or blockage of proline transporter TcAAAP069on parasite survival. Crystal violet (CV) was used for several years as a blood additive forprevention of transfusion transmitted Chagas disease and the protein synthesis inhibitionobserved by CV could be due to inhibition of amino acid uptake. In this work, we demonstratedthat CV enters at least in part through the proline permease TcAAAP069. CV inhibited prolinetransport and parasites overexpressing proline transporter were more sensitive to itstrypanocidal action. The protective effect of proline in oxidative stress situations led to a 3-foldincrease resistance when proline was added to the medium along with CV. In order to obtainother drugs that might have similar effects to CV, we performed a similarity-based virtualscreening, using the CV as query and different drug databases. So far, two of the obtainedcompounds proved to be effective as proline transport inhibitors that also had trypanocidaleffect. Another drug obtained with this strategy inhibited TcAAAP069 activity but lackedtrypanocidal effect. Taken together, these results show that it is possible to obtain newtrypanocidal compounds by drug repositioning using CV as a reference. Drug repositioning isone of the recommended strategies by the World Health Organization to fight neglecteddiseases, like Chagas disease, because costs and development time are significantly reducedfor its application in therapy. Supported by:CONICET

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