Identification of Novel Chemical Scaffolds Inhibiting Trypanothione Synthetase from Pathogenic Trypanosomatids.
BACKGROUND:The search for novel chemical entities targeting essential and parasite-specific pathways is considered a priority for neglected diseases such as trypanosomiasis and leishmaniasis. The thiol-dependent redox metabolism of trypanosomatids relies on bis-glutathionylspermidine [trypanothione,...
Published in: | PLOS Neglected Tropical Diseases |
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ftdoajarticles:oai:doaj.org/article:437dd6f537b74d759f740c4c444491a2 2023-05-15T15:11:52+02:00 Identification of Novel Chemical Scaffolds Inhibiting Trypanothione Synthetase from Pathogenic Trypanosomatids. Diego Benítez Andrea Medeiros Lucía Fiestas Esteban A Panozzo-Zenere Franziska Maiwald Kyriakos C Prousis Marina Roussaki Theodora Calogeropoulou Anastasia Detsi Timo Jaeger Jonas Šarlauskas Lucíja Peterlin Mašič Conrad Kunick Guillermo R Labadie Leopold Flohé Marcelo A Comini 2016-04-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0004617 https://doaj.org/article/437dd6f537b74d759f740c4c444491a2 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC4829233?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004617 https://doaj.org/article/437dd6f537b74d759f740c4c444491a2 PLoS Neglected Tropical Diseases, Vol 10, Iss 4, p e0004617 (2016) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2016 ftdoajarticles https://doi.org/10.1371/journal.pntd.0004617 2022-12-31T13:04:09Z BACKGROUND:The search for novel chemical entities targeting essential and parasite-specific pathways is considered a priority for neglected diseases such as trypanosomiasis and leishmaniasis. The thiol-dependent redox metabolism of trypanosomatids relies on bis-glutathionylspermidine [trypanothione, T(SH)2], a low molecular mass cosubstrate absent in the host. In pathogenic trypanosomatids, a single enzyme, trypanothione synthetase (TryS), catalyzes trypanothione biosynthesis, which is indispensable for parasite survival. Thus, TryS qualifies as an attractive drug target candidate. METHODOLOGY/PRINCIPAL FINDING:A library composed of 144 compounds from 7 different families and several singletons was screened against TryS from three major pathogen species (Trypanosoma brucei, Trypanosoma cruzi and Leishmania infantum). The screening conditions were adjusted to the TryS´ kinetic parameters and intracellular concentration of substrates corresponding to each trypanosomatid species, and/or to avoid assay interference. The screening assay yielded suitable Z' and signal to noise values (≥0.85 and ~3.5, respectively), and high intra-assay reproducibility. Several novel chemical scaffolds were identified as low μM and selective tri-tryp TryS inhibitors. Compounds displaying multi-TryS inhibition (N,N'-bis(3,4-substituted-benzyl) diamine derivatives) and an N5-substituted paullone (MOL2008) halted the proliferation of infective Trypanosoma brucei (EC50 in the nM range) and Leishmania infantum promastigotes (EC50 = 12 μM), respectively. A bis-benzyl diamine derivative and MOL2008 depleted intracellular trypanothione in treated parasites, which confirmed the on-target activity of these compounds. CONCLUSIONS/SIGNIFICANCE:Novel molecular scaffolds with on-target mode of action were identified as hit candidates for TryS inhibition. Due to the remarkable species-specificity exhibited by tri-tryp TryS towards the compounds, future optimization and screening campaigns should aim at designing and detecting, respectively, more ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 10 4 e0004617 |
institution |
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 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Diego Benítez Andrea Medeiros Lucía Fiestas Esteban A Panozzo-Zenere Franziska Maiwald Kyriakos C Prousis Marina Roussaki Theodora Calogeropoulou Anastasia Detsi Timo Jaeger Jonas Šarlauskas Lucíja Peterlin Mašič Conrad Kunick Guillermo R Labadie Leopold Flohé Marcelo A Comini Identification of Novel Chemical Scaffolds Inhibiting Trypanothione Synthetase from Pathogenic Trypanosomatids. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
BACKGROUND:The search for novel chemical entities targeting essential and parasite-specific pathways is considered a priority for neglected diseases such as trypanosomiasis and leishmaniasis. The thiol-dependent redox metabolism of trypanosomatids relies on bis-glutathionylspermidine [trypanothione, T(SH)2], a low molecular mass cosubstrate absent in the host. In pathogenic trypanosomatids, a single enzyme, trypanothione synthetase (TryS), catalyzes trypanothione biosynthesis, which is indispensable for parasite survival. Thus, TryS qualifies as an attractive drug target candidate. METHODOLOGY/PRINCIPAL FINDING:A library composed of 144 compounds from 7 different families and several singletons was screened against TryS from three major pathogen species (Trypanosoma brucei, Trypanosoma cruzi and Leishmania infantum). The screening conditions were adjusted to the TryS´ kinetic parameters and intracellular concentration of substrates corresponding to each trypanosomatid species, and/or to avoid assay interference. The screening assay yielded suitable Z' and signal to noise values (≥0.85 and ~3.5, respectively), and high intra-assay reproducibility. Several novel chemical scaffolds were identified as low μM and selective tri-tryp TryS inhibitors. Compounds displaying multi-TryS inhibition (N,N'-bis(3,4-substituted-benzyl) diamine derivatives) and an N5-substituted paullone (MOL2008) halted the proliferation of infective Trypanosoma brucei (EC50 in the nM range) and Leishmania infantum promastigotes (EC50 = 12 μM), respectively. A bis-benzyl diamine derivative and MOL2008 depleted intracellular trypanothione in treated parasites, which confirmed the on-target activity of these compounds. CONCLUSIONS/SIGNIFICANCE:Novel molecular scaffolds with on-target mode of action were identified as hit candidates for TryS inhibition. Due to the remarkable species-specificity exhibited by tri-tryp TryS towards the compounds, future optimization and screening campaigns should aim at designing and detecting, respectively, more ... |
format |
Article in Journal/Newspaper |
author |
Diego Benítez Andrea Medeiros Lucía Fiestas Esteban A Panozzo-Zenere Franziska Maiwald Kyriakos C Prousis Marina Roussaki Theodora Calogeropoulou Anastasia Detsi Timo Jaeger Jonas Šarlauskas Lucíja Peterlin Mašič Conrad Kunick Guillermo R Labadie Leopold Flohé Marcelo A Comini |
author_facet |
Diego Benítez Andrea Medeiros Lucía Fiestas Esteban A Panozzo-Zenere Franziska Maiwald Kyriakos C Prousis Marina Roussaki Theodora Calogeropoulou Anastasia Detsi Timo Jaeger Jonas Šarlauskas Lucíja Peterlin Mašič Conrad Kunick Guillermo R Labadie Leopold Flohé Marcelo A Comini |
author_sort |
Diego Benítez |
title |
Identification of Novel Chemical Scaffolds Inhibiting Trypanothione Synthetase from Pathogenic Trypanosomatids. |
title_short |
Identification of Novel Chemical Scaffolds Inhibiting Trypanothione Synthetase from Pathogenic Trypanosomatids. |
title_full |
Identification of Novel Chemical Scaffolds Inhibiting Trypanothione Synthetase from Pathogenic Trypanosomatids. |
title_fullStr |
Identification of Novel Chemical Scaffolds Inhibiting Trypanothione Synthetase from Pathogenic Trypanosomatids. |
title_full_unstemmed |
Identification of Novel Chemical Scaffolds Inhibiting Trypanothione Synthetase from Pathogenic Trypanosomatids. |
title_sort |
identification of novel chemical scaffolds inhibiting trypanothione synthetase from pathogenic trypanosomatids. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2016 |
url |
https://doi.org/10.1371/journal.pntd.0004617 https://doaj.org/article/437dd6f537b74d759f740c4c444491a2 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 10, Iss 4, p e0004617 (2016) |
op_relation |
http://europepmc.org/articles/PMC4829233?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004617 https://doaj.org/article/437dd6f537b74d759f740c4c444491a2 |
op_doi |
https://doi.org/10.1371/journal.pntd.0004617 |
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PLOS Neglected Tropical Diseases |
container_volume |
10 |
container_issue |
4 |
container_start_page |
e0004617 |
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1766342655278579712 |