Identification of Anti-Leishmanial Leads from Open Access Pathogen Box
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Date
2019-01
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Addis Ababa University
Abstract
Leishmaniasis is a vector-borne disease caused by an obligate intracellular protozoan of the genus Leishmania. The ranges of drugs available to treat this disease are limited; therefore, there is a substantial need to develop new medicines or drug combinations. Aiming to find potential anti-leishmanial leads, we screened MMV Pathogen Box for two strains of leishmania parasites. In this optimised, medium throughput primary screening assay, all 400 compounds were screened against promastigotes and amastigotes stages of L. donovani and L. aethiopica. The screen yielded a total of 16 hits with IC50 ranges from 0.01 to 0.555 μM on anti-promastigote assay and 0.05 to 0.7 μM on intracellular amastigote assay, respectively. Two compounds, known by MMV690102 and MMV688262 were identified as lead compounds for L. aethiopica and L. donovani. Cytotoxic effect of selected hits and synergistic effect of lead compounds with common reference drugs was also investigated. All selected compounds demonstrated good safety for the mammalian cell they were tested. The anti-TB drug (delamanid) showed synergistic effect with Amphoterecin B. This indicates the prospect of this compound for combination therapy. MMV690102 demonstrated inhibitory activity on both tested strains indicating its broad spectrum in activity. Future works should investigate antiamastigotes activity of those ‘hits’, which are not covered in the present study, and Identified lead compounds should progressed to other pre-clinical studies and their mechanism of action should be investigated using target based experiments.
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Keywords
Leishmania donovani, Lishmania aethiopica, promastigotes, Intracellular Amastigotes, MMV Pathogen Box, drug screening, in vitro