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Discovery of a Carbazole-Derived Lead Drug for Human African Trypanosomiasis
The protozoan parasite Trypanosoma brucei causes the fatal illness human African trypanosomiasis (HAT). Standard of care medications currently used to treat HAT have severe limitations, and there is a need to find new chemical entities that are active against infections of T. brucei. Following a “dr...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5000474/ https://www.ncbi.nlm.nih.gov/pubmed/27561392 http://dx.doi.org/10.1038/srep32083 |
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author | Thomas, Sarah M. Purmal, Andrei Pollastri, Michael Mensa-Wilmot, Kojo |
author_facet | Thomas, Sarah M. Purmal, Andrei Pollastri, Michael Mensa-Wilmot, Kojo |
author_sort | Thomas, Sarah M. |
collection | PubMed |
description | The protozoan parasite Trypanosoma brucei causes the fatal illness human African trypanosomiasis (HAT). Standard of care medications currently used to treat HAT have severe limitations, and there is a need to find new chemical entities that are active against infections of T. brucei. Following a “drug repurposing” approach, we tested anti-trypanosomal effects of carbazole-derived compounds called “Curaxins”. In vitro screening of 26 compounds revealed 22 with nanomolar potency against axenically cultured bloodstream trypanosomes. In a murine model of HAT, oral administration of compound 1 cured the disease. These studies established 1 as a lead for development of drugs against HAT. Pharmacological time-course studies revealed the primary effect of 1 to be concurrent inhibition of mitosis coupled with aberrant licensing of S-phase entry. Consequently, polyploid trypanosomes containing 8C equivalent of DNA per nucleus and three or four kinetoplasts were produced. These effects of 1 on the trypanosome are reminiscent of “mitotic slippage” or endoreplication observed in some other eukaryotes. |
format | Online Article Text |
id | pubmed-5000474 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-50004742016-09-07 Discovery of a Carbazole-Derived Lead Drug for Human African Trypanosomiasis Thomas, Sarah M. Purmal, Andrei Pollastri, Michael Mensa-Wilmot, Kojo Sci Rep Article The protozoan parasite Trypanosoma brucei causes the fatal illness human African trypanosomiasis (HAT). Standard of care medications currently used to treat HAT have severe limitations, and there is a need to find new chemical entities that are active against infections of T. brucei. Following a “drug repurposing” approach, we tested anti-trypanosomal effects of carbazole-derived compounds called “Curaxins”. In vitro screening of 26 compounds revealed 22 with nanomolar potency against axenically cultured bloodstream trypanosomes. In a murine model of HAT, oral administration of compound 1 cured the disease. These studies established 1 as a lead for development of drugs against HAT. Pharmacological time-course studies revealed the primary effect of 1 to be concurrent inhibition of mitosis coupled with aberrant licensing of S-phase entry. Consequently, polyploid trypanosomes containing 8C equivalent of DNA per nucleus and three or four kinetoplasts were produced. These effects of 1 on the trypanosome are reminiscent of “mitotic slippage” or endoreplication observed in some other eukaryotes. Nature Publishing Group 2016-08-26 /pmc/articles/PMC5000474/ /pubmed/27561392 http://dx.doi.org/10.1038/srep32083 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Thomas, Sarah M. Purmal, Andrei Pollastri, Michael Mensa-Wilmot, Kojo Discovery of a Carbazole-Derived Lead Drug for Human African Trypanosomiasis |
title | Discovery of a Carbazole-Derived Lead Drug for Human African Trypanosomiasis |
title_full | Discovery of a Carbazole-Derived Lead Drug for Human African Trypanosomiasis |
title_fullStr | Discovery of a Carbazole-Derived Lead Drug for Human African Trypanosomiasis |
title_full_unstemmed | Discovery of a Carbazole-Derived Lead Drug for Human African Trypanosomiasis |
title_short | Discovery of a Carbazole-Derived Lead Drug for Human African Trypanosomiasis |
title_sort | discovery of a carbazole-derived lead drug for human african trypanosomiasis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5000474/ https://www.ncbi.nlm.nih.gov/pubmed/27561392 http://dx.doi.org/10.1038/srep32083 |
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