Anti-trypanosomal activity and target validation of the M17 leucyl-aminopeptidase inhibitor DDD00057570 in Trypanosoma cruzi

Chagas disease, caused by the parasite Trypanosoma cruzi, affects millions of people worldwide and remains a challenging condition to treat due to limited efficacy and poor tolerance of existing drugs. Researchers have identified the major acidic M17 leucyl-aminopeptidase of T. cruzi as a potential drug target, although its pharmacological validation had not been achieved until now.

In this study, a compound called DDD00057570, originally discovered as an inhibitor of a similar enzyme found in Leishmania major, was evaluated against the T. cruzi enzyme and the parasite itself. The results demonstrated that DDD00057570 effectively inhibited the recombinant T. cruzi enzyme, with an IC50 of 2.7 ± 0.9 µM. Additionally, the compound reduced the proliferation of epimastigotes, the insect-stage form of the parasite, at a half-maximal effective concentration of 3.7 ± 1.1 µM.

Furthermore, researchers created modified parasites that overexpressed the target enzyme, which showed twice the resistance to DDD00057570 compared to the wild-type parasites, highlighting the enzyme's role as a primary target within the living parasite. When administered to infected mammalian cells, the compound successfully decreased the release of trypomastigotes, the stage responsible for transmitting the parasite to the mammalian host.

At a half-maximal effective concentration of 1.3 ± 0.6 µM, DDD00057570 exhibited a selectivity index of approximately 32 when compared to CHO-K1 mammalian host cells, indicating a promising level of toxicity reduction.

In conclusion, DDD00057570 has been identified as a selective lead structure for further investigation as a potential treatment for Chagas disease. These findings validate the M17 leucyl-aminopeptidase as a viable target for new therapies, offering hope for a more effective treatment method against this debilitating condition.