Abstract
Since many of the currently available antileishmanial treatments exhibit toxicity, low effectiveness, and resistance, search and validation of new therapeutic targets allowing the development of innovative drugs have become a worldwide priority. This work presents a structure-based drug discovery strategy to validate the Lmj_04_BRCT domain as a novel therapeutic target in Leishmania spp. The structure of this domain was explored using homology modeling, virtual screening, and molecular dynamics studies. Candidate compounds were validated in vitro using promastigotes of Leishmania major, L. amazonensis, and L. infantum, as well as primary mouse macrophages infected with L. major. The novel inhibitor CPE2 emerged as the most active of a group of compounds against Leishmania, being able to significantly reduce the viability of promastigotes. CPE2 was also active against the intracellular forms of the parasites and significantly reduced parasite burden in murine macrophages without exhibiting toxicity in host cells. Furthermore, L. major promastigotes treated with CPE2 showed significant lower expression levels of several genes (α-tubulin, Cyclin CYCA, and Yip1) related to proliferation and treatment resistance. Our in silico and in vitro studies suggest that the Lmj_04_BRCT domain and its here disclosed inhibitors are new potential therapeutic options against leishmaniasis.
Highlights
Leishmaniasis is among the infectious diseases considered by the World Health Organization (WHO) as neglected tropical diseases (NTDs) [1]
After the models were prepared, several known ligands of the BRCT domain were docked as described in the materials and methods
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Summary
Leishmaniasis is among the infectious diseases considered by the World Health Organization (WHO) as neglected tropical diseases (NTDs) [1]. Taking into consideration how all available treatments are largely hampered with disadvantages that have made impossible the eradication of this disease, the search and validation of newer therapeutic targets has become a worldwide priority In this sense, one of the most important advancements in the field of leishmaniasis drug development took place in 2005 with the sequencing of the complete genome of L. major [3] that enabled the scientific community to scan the parasite genome to search for suitable drug targets. Leishmanicidal activity was reported for both promastigote and amastigote stages, along with extremely low toxicity in mammalianderived cells These data together with our generated models of BRCT domain allow us to propose a new therapeutic target in Leishmania. The results from this work may allow progress in the development of useful drugs against this disease
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