A Multi-Species Phenotypic Screening Assay for Leishmaniasis Drug Discovery Shows That Active Compounds Display a High Degree of Species-Specificity

Alcantara, Laura M, Ferreira, Thalita CS, Fontana, Vanessa ORCID: 0000-0002-0146-9113, Chatelain, Eric, Moraes, Carolina B and Freitas-Junior, Lucio H (2020) A Multi-Species Phenotypic Screening Assay for Leishmaniasis Drug Discovery Shows That Active Compounds Display a High Degree of Species-Specificity. MOLECULES, 25 (11). E2551-. ISSN 1420-3049, 1420-3049

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Abstract

High genetic and phenotypic variability between <i>Leishmania</i> species and strains within species make the development of broad-spectrum antileishmanial drugs challenging. Thus, screening panels consisting of several diverse <i>Leishmania</i> species can be useful in enabling compound prioritization based on their spectrum of activity. In this study, a robust and reproducible high content assay was developed, and 1280 small molecules were simultaneously screened against clinically relevant cutaneous and visceral species: <i>L. amazonensis</i>, <i>L. braziliensis</i>, and <i>L. donovani</i>. The assay is based on THP-1 macrophages infected with stationary phase promastigotes and posterior evaluation of both compound antileishmanial activity and host cell toxicity. The profile of compound activity was species-specific, and out of 51 active compounds, only 14 presented broad-spectrum activity against the three species, with activities ranging from 52% to 100%. Notably, the compounds CB1954, Clomipramine, Maprotiline, Protriptyline, and ML-9 presented pan-leishmanial activity, with efficacy greater than 70%. The results highlight the reduced number of compound classes with pan-leishmanial activity that might be available from diversity libraries, emphasizing the need to screen active compounds against a panel of species and strains. The assay reported here can be adapted to virtually any <i>Leishmania</i> species without the need for genetic modification of parasites, providing the basis for the discovery of broad spectrum anti-leishmanial agents.

Item Type:	Article
Uncontrolled Keywords:	Leishmania, leishmaniasis drug discovery, phenotypic screening, Leishmania species
Depositing User:	Symplectic Admin
Date Deposited:	02 Jul 2020 09:48
Last Modified:	07 Dec 2024 09:55
DOI:	10.3390/molecules25112551
Open Access URL:	https://www.mdpi.com/1420-3049/25/11/2551
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3090635