Development of a model plataform for the search of leishmanicidal compounds based on the selective inhibition of dihydroorotate dehydrogenase

Abstract

The Leishmaniasis correspond to a group of diseases considered neglected tropical diseases characterized by a lack of investment in the development of new therapies by both the public sector and the private sector. In this context, the academy has played an important role in the search for new strategies for prevention and treatment, in particular, the identification and validation of potential macromolecular targets, beyond the search for new bioactive compound that can act as prototypes for the development of new therapies. Within this context, our laboratory has been working on the characterization and evaluation of dihydroorotate dehydrogenase (DHODH) as a potential therapeutic target for diseases caused by trypanosomes, in particular, Leishmaniasis. With the application of molecular biology, biochemistry, spectroscopy and crystallography, X- rays could characterize the DHODH enzyme Leishmania major (LmDHODH). This enzyme plays a key role in the synthesis of pyrimidine nucleotides, which makes this enzyme an important target in the development of new drug candidates that may play antiproliferative and antiparasitic activities. The structural and functional assessment of LmDHODH and different mutants allowed us to use in vitro and in silico in search of potent and selective ligands against the parasite enzyme. Two molecules, in particular so-called LCPSP3027 LCPVL898 and were identified as inhibitors LmDHOH IC50 of 1.66 ± 0.03 mM and 2.82 ± 0.02 mM , respectively. These ligands showed leishmanicidal activity in vitro cultures of Leishmania (V.) braziliensis promastigote form in (LD50 of 2.1 mM for LCPSP3027 LD50 and 2.8 mM for LCPVL898), proved not cytotoxic to macrophages and amastigotes studies showed a reduction significant indices of infectivity. With the development of this project we intend to continue their studies, based on the synthesis of the compounds and LCPSP3027 LCPVL898 and its analogs, followed by the evaluation of the inhibitory potential for new molecules and the development of a formulation, and the first pre - clinical trials. This project aims to contribute to the construction of knowledge about the potential of selective inhibition of dihydroorotate dehydrogenase as a therapeutic strategy in the fight against leishmaniasis. (AU)