Ponente
Descripción
Leishmania major leucyl-aminopeptidase M17 (LmLAP) is a promising therapeutic
target for the development of new anti-leishmanial agents. The drugs currently used are
inefficient and highly toxic, for this reason the development of inhibitors as possible
therapeutic agents remains an attractive field of study. This work aims to identify potent
and selective inhibitors of LmLAP with anti-parasitic effect. A recombinant variant of
LmLAP was obtained in Escherichia coli and a selection of synthetic chemical
compounds was performed by high-flow screening using RapidFire-Mass
Spectrometry. After the dose-response studies we selected the compound
DDD000057570 as a potent LmLAP inhibitor with an IC50 of 3.39 µM. In vitro antiparasitic inhibition tests were carried out on amastigotes of Leishmania at a
concentration of 50 µM, obtaining an inhibitory effect of 98.4%. Compound
DDD00057570 was identified as a good inhibitor against Leishmania amastigotes with
an EC50 of 7.41 µM. The cytotoxicity test carried out with the compounds against
mammalian cell cultures: Hs-HepG2, showed that the compound does not have a
cytotoxic effect on these mammalian cells. In addition, selectivity studies of
DDD00057570 against the human variant of this enzyme were carried out, obtaining
that this compound did not have any inhibitory effect against Hs-LAP. Therefore, the
compound DDD00057570 can be considered a starting point for the development of a
future therapeutic agent with anti-leishmanial activity.
