The Akt-like kinase of Leishmania spp. is a cytoplasmic orthologous protein of the serine/threonine kinase B-PKB/human-Akt group, which is involved in the cellular survival of these parasites. By the application of a computational strategy we obtained two specific inhibitors of the Akt-like protein of L. panamensis (UBMC1 and UBMC4), which are predicted to bind specifically to the pleckstrin domain (PH) of the enzyme. We show that the Akt-like of Leishmania panamensis is phospho-activated in parasites under nutritional and thermic stress, this phosphorylation is blocked by the UBMC1 and UMBC2 and such inhibition leads to cell death. Amongst the effects caused by the inhibitors on the parasites we found high percentage of hypodiploidy and loss of mitochondrial membrane potential. Ultrastructural studies showed highly vacuolated cytoplasm, as well as shortening of the flagellum, loss of nuclear membrane integrity and DNA fragmentation. Altogether the presented results suggest that the cell death caused by UMBC1 and UMBC4 may be associated to an apoptosis-like process. The compounds present an inhibitory concentration (IC) over intracellular amastigotes of L. panamensis of 9.2±0.8μM for UBMC1 and 4.6±1.9μM for UBMC4. The cytotoxic activity for UBMC1 and UBMC4 in human macrophages derived from monocytes (huMDM) was 29±1.2μM and >40μM respectively. Our findings strongly support that the presented compounds can be plausible candidates as a new therapeutic alternative for the inhibition of specific kinases of the parasite.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.