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Chalcones identify cTXNPx as a potential antileishmanial drug target
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’...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8664226/ https://www.ncbi.nlm.nih.gov/pubmed/34780470 http://dx.doi.org/10.1371/journal.pntd.0009951 |
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author | 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. |
author_facet | 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. |
author_sort | Escrivani, Douglas O. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8664226 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-86642262021-12-11 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. PLoS Negl Trop Dis Research Article 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. Public Library of Science 2021-11-15 /pmc/articles/PMC8664226/ /pubmed/34780470 http://dx.doi.org/10.1371/journal.pntd.0009951 Text en © 2021 Escrivani et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article 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. Chalcones identify cTXNPx as a potential antileishmanial drug target |
title | Chalcones identify cTXNPx as a potential antileishmanial drug target |
title_full | Chalcones identify cTXNPx as a potential antileishmanial drug target |
title_fullStr | Chalcones identify cTXNPx as a potential antileishmanial drug target |
title_full_unstemmed | Chalcones identify cTXNPx as a potential antileishmanial drug target |
title_short | Chalcones identify cTXNPx as a potential antileishmanial drug target |
title_sort | chalcones identify ctxnpx as a potential antileishmanial drug target |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8664226/ https://www.ncbi.nlm.nih.gov/pubmed/34780470 http://dx.doi.org/10.1371/journal.pntd.0009951 |
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