Computer-guided drug repositioning for the treatment of neglected tropical diseases

ALBERCA, LUCAS NICOLÁS

Lyon

Encuentro; Biovision 2016 The World Life Sciences Forum; 2016

Fondation pour l?université de Lyon

Chagas disease is a parasitic infection caused by the protozoa Trypanosoma cruzi. At present, there are about 7 million people infected, mostly of them in Latin America. This disease is treated by only one of two drugs, nifurtimox and benznidazole, which have severe side effects and limited effectiveness in adults in chronic phase.Polyamines are essential substances for T. cruzi, however, it has been found that this parasite lacks the enzymes responsible for the complete biosynthesis of polyamines, demonstrating a strict dependence for polyamine transport from the host. This particular feature makes the transporters of polyamines on specific molecular targets.Our aim in this research is find approved drugs for another therapeutic indication that can be used to the treatment of Chagas disease and overcome the limitations of current drugs. This strategy, known as drug repositioning, may be obtained significant advantages in the cost and time required for the approving of a new treatment.We have been compiled a literature database containing polyamine analogues that have already been evaluated against the proliferation of the parasite. From this database we have inferred computational models capable of recognizing polyamine analogs with inhibitory activity against T. cruzi. The best models have been applied in a virtual screening campaign to identify trypanocidal compounds among approved drugs.We have selected 5 drugs for the evaluation in cellular and in vitro models. 3 of the tested drugs showed inhibitory effect on the proliferation of T. cruzi (epimastigotes and trypomastigotes) and the uptake of putrescine by the parasite.