INSTITUTO DE INVESTIGACIONES EN CIENCIAS DE LA SALUD
Unidad Ejecutora - UE
3-Hydroxykynurenine, a Tryptophan Metabolite Generated during the Infection, Is Active Against Trypanosoma cruzi
INSFRAN, CONSTANZA; FRETES, RICARDO E.; MOTRAN, CLAUDIA C.; KNUBEL, CAROLINA P.; DIAZ LUJAN, CINTIA; CERVI, LAURA; MARTINEZ, FERNANDO F.; THEUMER, MARTIN G.
ACS Medicinal Chemistry Letters
The antiparasitic activity of 3-hydroxykynurenine (3-HK), one of the majortryptophan catabolites of the kynurenine pathway, against both Trypanosoma cruzi evolutiveforms that are important for human infection, trypomastigotes (Tps) and amastigotes (Am),possible targets in the parasite and the drug toxicity to mammalian cells have beeninvestigated. 3-HK showed a potent activity against Am with IC50 values in the micromolarconcentration 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 susceptibleto 3-HK than bloodstream Tps. In addition, 3-HK showed activity against Tps and Am, atconcentrations that did not exhibit toxicity to mammalian cells. Ultrastructural analysis andflow cytometry studies indicated that Am and Tps mitochondrion and nuclei contain 3-HKtargets. The potency and selectivity of 3-HK, which is generated during T. cruzi infection in human and mice, suggest that 3-HKmay be a suitable candidate for drug research and development for Chagas disease.KEYWORDS: Chagas disease, chemotherapy, drug toxicity, amastigotes, trypomastigotes