-Hydroxykynurenine, a Tryptophan Metabolite Generated During the Infection, Is Active Against Trypanosoma cruzi

; KNUBEL, CAROLINA;; MARTINEZ FF; DIAZ LUJAN C; FRETES RE,; CERVI L; MOTRAN CC

ACS Medicinal Chemistry Letters

Elsevier

Lugar: New York; Año: 2017

1948-5875

bstractThe antiparasitic activity of 3-hydroxykynurenine (3-HK), one of the major tryptophan catabolites of the kynurenine pathway, against both Trypanosoma cruzi evolutive forms that are important for human infection, trypomastigotes (Tps) and amastigotes (Am), possible targets in the parasite and the drug toxicity to mammalian cells have been investigated. 3-HK showed a potent activity against Am with IC50 values in the micromolar concentration range, while the IC50 values to cause Tps death was ∼6000-times higher, indicating that the replicative form present in the vertebrate hosts is much more susceptible to 3-HK than bloodstream Tps. In addition, 3-HK showed activity against Tps and Am, at concentrations that did not exhibit toxicity to mammalian cells. Ultrastructural analysis and flow cytometry studies indicated that Am and Tps mitochondrion and nuclei contain 3-HK targets. The potency and selectivity of 3-HK, which is generated during T. cruzi infection in human and mice