Unveiling six potent and highly selective antileishmanial agents via the open source compound collection 'Pathogen Box' against antimony-sensitive and -resistant Leishmania braziliensis.

Autor: Souza Silva JA; Instituto René Rachou - Fiocruz Minas, Av. Augusto de Lima, 1715, Belo Horizonte, 30190-009, MG, Brazil. Electronic address: julianossilva@ufmg.br., Tunes LG; Instituto René Rachou - Fiocruz Minas, Av. Augusto de Lima, 1715, Belo Horizonte, 30190-009, MG, Brazil. Electronic address: tunes@ynamlab.org., Coimbra RS; Instituto René Rachou - Fiocruz Minas, Av. Augusto de Lima, 1715, Belo Horizonte, 30190-009, MG, Brazil. Electronic address: roney.coimbra@fiocruz.br., Ascher DB; Structural Biology and Bioinformatics, Department of Biochemistry and Molecular Biology, The University of Melbourne, Bio21 Institute, 30 Flemington Rd, Parkville, VIC 3052, Melbourne, Australia; Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, VIC 3004, Melbourne, Australia. Electronic address: david.ascher@unimelb.edu.au., Pires DEV; Instituto René Rachou - Fiocruz Minas, Av. Augusto de Lima, 1715, Belo Horizonte, 30190-009, MG, Brazil; School of Computing and Information Systems, The University of Melbourne, Doug McDonell Building, VIC 3010, Parkville, Melbourne, Australia. Electronic address: douglas.pires@unimelb.edu.au., Monte-Neto RL; Instituto René Rachou - Fiocruz Minas, Av. Augusto de Lima, 1715, Belo Horizonte, 30190-009, MG, Brazil. Electronic address: rubens.monte@fiocruz.br.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2021 Jan; Vol. 133, pp. 111049. Date of Electronic Publication: 2020 Dec 04.
DOI: 10.1016/j.biopha.2020.111049
Abstrakt: Despite all efforts to provide new chemical entities to tackle leishmaniases, we are still dependent on a the limited drug arsenal, together with drawbacks like toxicity and drug-resistant parasites. Collaborative drug discovery emerged as an option to speed up the way to find alternative antileishmanial agents. This is the case of Medicines for Malaria Ventures - MMV, that promotes an open source drug discovery initiative to fight diseases worldwide. Here, we screened 400 compounds from 'Pathogen Box' (PBox) collection against Leishmania braziliensis, the main etiological agent of cutaneous leishmaniasis in Brazil. Twenty-three compounds were able to inhibit ≥ 80 % L. braziliensis growth at 5 μM. Six out of the PBox selected 23 compounds were found to be highly selective against L. braziliensis intracellular amastigotes with selectivity index varying from > 104 to > 746 and IC 50 s ranging from 47 to 480 nM. The compounds were also active against antimony-resistant L. braziliensis isolated from the field or laboratory selected mutants, revealing the potential on treating patients infected with drug resistant parasites. Most of the selected compounds were known to be active against kinetoplastids, however, two compounds (MMV688703 and MMV676477) were part of toxoplasmosis and tuberculosis 'PBox' disease set, reinforcing the potential of phenotyping screening to unveil drug repurposing. Here we applied a computational prediction of pharmacokinetic properties using the ADMET predictor pkCSM (http://biosig.unimelb.edu.au/pkcsm/). The tool offered clues on potential drug development needs and can support further in vivo studies. Molecular docking analysis identified CRK3 (LbrM.35.0660), CYP450 (LbrM.30.3580) and PKA (LbrM.18.1180) as L. braziliensis targets for MMV676604, MMV688372 and MMV688703, respectively. Compounds from 'Pathogen Box' thus represents a new hope for novel (or repurposed) small molecules source to tackle leishmaniases.
(Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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