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Chalcones identify cTXNPx as a potential antileishmanial drug target

Escrivani, Douglas O.; Charlton, Rebecca L.; Caruso, Marjolly B.; Burle-Caldas, Gabriela A.; Borsodi, Maria Paula G.; Zingali, Russolina B.; Arruda-Costa, Natalia; Palmeira-Mello, Marcos V.; de Jesus, Jéssica B.; Souza, Alessandra M.T.; Abrahim-Vieira, Bárbara; Freitag-Pohl, Stefanie; Pohl, Ehmke; Denny, Paul W.; Rossi-Bergmann, Bartira; Steel, Patrick G.

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Authors

Douglas O. Escrivani

Rebecca L. Charlton

Marjolly B. Caruso

Gabriela A. Burle-Caldas

Maria Paula G. Borsodi

Russolina B. Zingali

Natalia Arruda-Costa

Marcos V. Palmeira-Mello

Jéssica B. de Jesus

Alessandra M.T. Souza

Bárbara Abrahim-Vieira

Bartira Rossi-Bergmann

Patrick G. Steel



Abstract

With current drug treatments failing due to toxicity, low efficacy and resistance; leishmaniasis is a major global health challenge that desperately needs new validated drug targets. Inspired by activity of the natural chalcone 2’,6’-dihydroxy-4’-methoxychalcone (DMC), the nitro-analogue, 3-nitro-2’,4’,6’- trimethoxychalcone (NAT22, 1c) was identified as potent broad spectrum antileishmanial drug lead. Structural modification provided an alkyne containing chemical probe that labelled a protein within the parasite that was confirmed as cytosolic tryparedoxin peroxidase (cTXNPx). Crucially, labelling is observed in both promastigote and intramacrophage amastigote life forms, with no evidence of host macrophage toxicity. Incubation of the chalcone in the parasite leads to ROS accumulation and parasite death. Deletion of cTXNPx, by CRISPR-Cas9, dramatically impacts upon the parasite phenotype and reduces the antileishmanial activity of the chalcone analogue. Molecular docking studies with a homology model of in-silico cTXNPx suggest that the chalcone is able to bind in the putative active site hindering access to the crucial cysteine residue. Collectively, this work identifies cTXNPx as an important target for antileishmanial chalcones.

Citation

Escrivani, D. O., Charlton, R. L., Caruso, M. B., Burle-Caldas, G. A., Borsodi, M. P. G., Zingali, R. B., …Steel, P. G. (2021). Chalcones identify cTXNPx as a potential antileishmanial drug target. PLoS Neglected Tropical Diseases, 15(11), Article e0009951. https://doi.org/10.1371/journal.pntd.0009951

Journal Article Type Article
Acceptance Date Oct 26, 2021
Online Publication Date Nov 1, 2021
Publication Date 2021
Deposit Date Nov 16, 2021
Publicly Available Date Jan 17, 2022
Journal PLOS Neglected Tropical Diseases
Print ISSN 1935-2727
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 15
Issue 11
Article Number e0009951
DOI https://doi.org/10.1371/journal.pntd.0009951

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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/

Copyright Statement
© 2021 Escrivani et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.







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