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-analo...
Published in: | PLOS Neglected Tropical Diseases |
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ftdoajarticles:oai:doaj.org/article:97dcebeea4914662b9ca60f477d72118 2023-05-15T15:06:46+02:00 Chalcones identify cTXNPx as a potential antileishmanial drug target. 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 Stefanie Freitag-Pohl Ehmke Pohl Paul W Denny Bartira Rossi-Bergmann Patrick G Steel 2021-11-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0009951 https://doaj.org/article/97dcebeea4914662b9ca60f477d72118 EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0009951 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0009951 https://doaj.org/article/97dcebeea4914662b9ca60f477d72118 PLoS Neglected Tropical Diseases, Vol 15, Iss 11, p e0009951 (2021) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2021 ftdoajarticles https://doi.org/10.1371/journal.pntd.0009951 2022-12-31T15:47:11Z 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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 15 11 e0009951 |
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Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 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 Stefanie Freitag-Pohl Ehmke Pohl Paul W Denny Bartira Rossi-Bergmann Patrick G Steel Chalcones identify cTXNPx as a potential antileishmanial drug target. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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 |
Article in Journal/Newspaper |
author |
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 Stefanie Freitag-Pohl Ehmke Pohl Paul W Denny Bartira Rossi-Bergmann Patrick G Steel |
author_facet |
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 Stefanie Freitag-Pohl Ehmke Pohl Paul W Denny Bartira Rossi-Bergmann Patrick G Steel |
author_sort |
Douglas O Escrivani |
title |
Chalcones identify cTXNPx as a potential antileishmanial drug target. |
title_short |
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_sort |
chalcones identify ctxnpx as a potential antileishmanial drug target. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2021 |
url |
https://doi.org/10.1371/journal.pntd.0009951 https://doaj.org/article/97dcebeea4914662b9ca60f477d72118 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 15, Iss 11, p e0009951 (2021) |
op_relation |
https://doi.org/10.1371/journal.pntd.0009951 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0009951 https://doaj.org/article/97dcebeea4914662b9ca60f477d72118 |
op_doi |
https://doi.org/10.1371/journal.pntd.0009951 |
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PLOS Neglected Tropical Diseases |
container_volume |
15 |
container_issue |
11 |
container_start_page |
e0009951 |
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1766338318656602112 |