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Spiro-containing derivatives show antiparasitic activity against Trypanosoma brucei through inhibition of the trypanothione reductase enzyme

Trypanothione reductase (TR) is a key enzyme that catalyzes the reduction of trypanothione, an antioxidant dithiol that protects Trypanosomatid parasites from oxidative stress induced by mammalian host defense systems. TR is considered an attractive target for the development of novel anti-parasitic...

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Autores principales: Turcano, Lorenzo, Battista, Theo, De Haro, Esther Torrente, Missineo, Antonino, Alli, Cristina, Paonessa, Giacomo, Colotti, Gianni, Harper, Steven, Fiorillo, Annarita, Ilari, Andrea, Bresciani, Alberto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269337/
https://www.ncbi.nlm.nih.gov/pubmed/32437349
http://dx.doi.org/10.1371/journal.pntd.0008339
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author Turcano, Lorenzo
Battista, Theo
De Haro, Esther Torrente
Missineo, Antonino
Alli, Cristina
Paonessa, Giacomo
Colotti, Gianni
Harper, Steven
Fiorillo, Annarita
Ilari, Andrea
Bresciani, Alberto
author_facet Turcano, Lorenzo
Battista, Theo
De Haro, Esther Torrente
Missineo, Antonino
Alli, Cristina
Paonessa, Giacomo
Colotti, Gianni
Harper, Steven
Fiorillo, Annarita
Ilari, Andrea
Bresciani, Alberto
author_sort Turcano, Lorenzo
collection PubMed
description Trypanothione reductase (TR) is a key enzyme that catalyzes the reduction of trypanothione, an antioxidant dithiol that protects Trypanosomatid parasites from oxidative stress induced by mammalian host defense systems. TR is considered an attractive target for the development of novel anti-parasitic agents as it is essential for parasite survival but has no close homologue in humans. We report here the identification of spiro-containing derivatives as inhibitors of TR from Trypanosoma brucei (TbTR), the parasite responsible for Human African Trypanosomiasis. The hit series, identified by high throughput screening, was shown to bind TbTR reversibly and to compete with the trypanothione (TS(2)) substrate. The prototype compound 1 from this series was also found to impede the growth of Trypanosoma brucei parasites in vitro. The X-ray crystal structure of TbTR in complex with compound 1 solved at 1.98 Å allowed the identification of the hydrophobic pocket where the inhibitor binds, placed close to the catalytic histidine (His 461’) and lined by Trp21, Val53, Ile106, Tyr110 and Met113. This new inhibitor is specific for TbTR and no activity was detected against the structurally similar human glutathione reductase (hGR). The central spiro scaffold is known to be suitable for brain active compounds in humans thus representing an attractive starting point for the future treatment of the central nervous system stage of T. brucei infections.
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spelling pubmed-72693372020-06-12 Spiro-containing derivatives show antiparasitic activity against Trypanosoma brucei through inhibition of the trypanothione reductase enzyme Turcano, Lorenzo Battista, Theo De Haro, Esther Torrente Missineo, Antonino Alli, Cristina Paonessa, Giacomo Colotti, Gianni Harper, Steven Fiorillo, Annarita Ilari, Andrea Bresciani, Alberto PLoS Negl Trop Dis Research Article Trypanothione reductase (TR) is a key enzyme that catalyzes the reduction of trypanothione, an antioxidant dithiol that protects Trypanosomatid parasites from oxidative stress induced by mammalian host defense systems. TR is considered an attractive target for the development of novel anti-parasitic agents as it is essential for parasite survival but has no close homologue in humans. We report here the identification of spiro-containing derivatives as inhibitors of TR from Trypanosoma brucei (TbTR), the parasite responsible for Human African Trypanosomiasis. The hit series, identified by high throughput screening, was shown to bind TbTR reversibly and to compete with the trypanothione (TS(2)) substrate. The prototype compound 1 from this series was also found to impede the growth of Trypanosoma brucei parasites in vitro. The X-ray crystal structure of TbTR in complex with compound 1 solved at 1.98 Å allowed the identification of the hydrophobic pocket where the inhibitor binds, placed close to the catalytic histidine (His 461’) and lined by Trp21, Val53, Ile106, Tyr110 and Met113. This new inhibitor is specific for TbTR and no activity was detected against the structurally similar human glutathione reductase (hGR). The central spiro scaffold is known to be suitable for brain active compounds in humans thus representing an attractive starting point for the future treatment of the central nervous system stage of T. brucei infections. Public Library of Science 2020-05-21 /pmc/articles/PMC7269337/ /pubmed/32437349 http://dx.doi.org/10.1371/journal.pntd.0008339 Text en © 2020 Turcano et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://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
Turcano, Lorenzo
Battista, Theo
De Haro, Esther Torrente
Missineo, Antonino
Alli, Cristina
Paonessa, Giacomo
Colotti, Gianni
Harper, Steven
Fiorillo, Annarita
Ilari, Andrea
Bresciani, Alberto
Spiro-containing derivatives show antiparasitic activity against Trypanosoma brucei through inhibition of the trypanothione reductase enzyme
title Spiro-containing derivatives show antiparasitic activity against Trypanosoma brucei through inhibition of the trypanothione reductase enzyme
title_full Spiro-containing derivatives show antiparasitic activity against Trypanosoma brucei through inhibition of the trypanothione reductase enzyme
title_fullStr Spiro-containing derivatives show antiparasitic activity against Trypanosoma brucei through inhibition of the trypanothione reductase enzyme
title_full_unstemmed Spiro-containing derivatives show antiparasitic activity against Trypanosoma brucei through inhibition of the trypanothione reductase enzyme
title_short Spiro-containing derivatives show antiparasitic activity against Trypanosoma brucei through inhibition of the trypanothione reductase enzyme
title_sort spiro-containing derivatives show antiparasitic activity against trypanosoma brucei through inhibition of the trypanothione reductase enzyme
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269337/
https://www.ncbi.nlm.nih.gov/pubmed/32437349
http://dx.doi.org/10.1371/journal.pntd.0008339
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