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...
Published in: | PLOS Neglected Tropical Diseases |
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ftdoajarticles:oai:doaj.org/article:6fee285090df47ca90b7a67167e262d5 2023-05-15T15:10:07+02:00 Spiro-containing derivatives show antiparasitic activity against Trypanosoma brucei through inhibition of the trypanothione reductase enzyme. Lorenzo Turcano Theo Battista Esther Torrente De Haro Antonino Missineo Cristina Alli Giacomo Paonessa Gianni Colotti Steven Harper Annarita Fiorillo Andrea Ilari Alberto Bresciani 2020-05-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0008339 https://doaj.org/article/6fee285090df47ca90b7a67167e262d5 EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0008339 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0008339 https://doaj.org/article/6fee285090df47ca90b7a67167e262d5 PLoS Neglected Tropical Diseases, Vol 14, Iss 5, p e0008339 (2020) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2020 ftdoajarticles https://doi.org/10.1371/journal.pntd.0008339 2022-12-31T06:00:48Z 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 (TS2) 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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Spiro ENVELOPE(-59.000,-59.000,-62.267,-62.267) PLOS Neglected Tropical Diseases 14 5 e0008339 |
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 Lorenzo Turcano Theo Battista Esther Torrente De Haro Antonino Missineo Cristina Alli Giacomo Paonessa Gianni Colotti Steven Harper Annarita Fiorillo Andrea Ilari Alberto Bresciani Spiro-containing derivatives show antiparasitic activity against Trypanosoma brucei through inhibition of the trypanothione reductase enzyme. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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 (TS2) 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. |
format |
Article in Journal/Newspaper |
author |
Lorenzo Turcano Theo Battista Esther Torrente De Haro Antonino Missineo Cristina Alli Giacomo Paonessa Gianni Colotti Steven Harper Annarita Fiorillo Andrea Ilari Alberto Bresciani |
author_facet |
Lorenzo Turcano Theo Battista Esther Torrente De Haro Antonino Missineo Cristina Alli Giacomo Paonessa Gianni Colotti Steven Harper Annarita Fiorillo Andrea Ilari Alberto Bresciani |
author_sort |
Lorenzo Turcano |
title |
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_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_sort |
spiro-containing derivatives show antiparasitic activity against trypanosoma brucei through inhibition of the trypanothione reductase enzyme. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2020 |
url |
https://doi.org/10.1371/journal.pntd.0008339 https://doaj.org/article/6fee285090df47ca90b7a67167e262d5 |
long_lat |
ENVELOPE(-59.000,-59.000,-62.267,-62.267) |
geographic |
Arctic Spiro |
geographic_facet |
Arctic Spiro |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 14, Iss 5, p e0008339 (2020) |
op_relation |
https://doi.org/10.1371/journal.pntd.0008339 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0008339 https://doaj.org/article/6fee285090df47ca90b7a67167e262d5 |
op_doi |
https://doi.org/10.1371/journal.pntd.0008339 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
14 |
container_issue |
5 |
container_start_page |
e0008339 |
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1766341168208019456 |