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Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation
Some 1,3-diarylureas and 1-((1,4-trans)−4-aryloxycyclohexyl)−3-arylureas (cHAUs) activate heme-regulated kinase causing protein synthesis inhibition via phosphorylation of the eukaryotic translation initiation factor 2 (eIF2) in mammalian cancer cells. To evaluate if these agents have potential to i...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861040/ https://www.ncbi.nlm.nih.gov/pubmed/29559670 http://dx.doi.org/10.1038/s41598-018-23259-9 |
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author | Machado, Fabricio Castro Franco, Caio Haddad dos Santos Neto, Jose Vitorino Dias-Teixeira, Karina Luiza Moraes, Carolina Borsoi Lopes, Ulisses Gazos Aktas, Bertal Huseyin Schenkman, Sergio |
author_facet | Machado, Fabricio Castro Franco, Caio Haddad dos Santos Neto, Jose Vitorino Dias-Teixeira, Karina Luiza Moraes, Carolina Borsoi Lopes, Ulisses Gazos Aktas, Bertal Huseyin Schenkman, Sergio |
author_sort | Machado, Fabricio Castro |
collection | PubMed |
description | Some 1,3-diarylureas and 1-((1,4-trans)−4-aryloxycyclohexyl)−3-arylureas (cHAUs) activate heme-regulated kinase causing protein synthesis inhibition via phosphorylation of the eukaryotic translation initiation factor 2 (eIF2) in mammalian cancer cells. To evaluate if these agents have potential to inhibit trypanosome multiplication by also affecting the phosphorylation of eIF2 alpha subunit (eIF2α), we tested 25 analogs of 1,3-diarylureas and cHAUs against Trypanosoma cruzi, the agent of Chagas disease. One of them (I-17) presented selectivity close to 10-fold against the insect replicative forms and also inhibited the multiplication of T. cruzi inside mammalian cells with an EC(50) of 1–3 µM and a selectivity of 17-fold. I-17 also prevented replication of African trypanosomes (Trypanosoma brucei bloodstream and procyclic forms) at similar doses. It caused changes in the T. cruzi morphology, arrested parasite cell cycle in G1 phase, and promoted phosphorylation of eIF2α with a robust decrease in ribosome association with mRNA. The activity against T. brucei also implicates eIF2α phosphorylation, as replacement of WT-eIF2α with a non-phosphorylatable eIF2α, or knocking down eIF2 protein kinase-3 by RNAi increased resistance to I-17. Therefore, we demonstrate that eIF2α phosphorylation can be engaged to develop trypanosome-static agents in general, and particularly by interfering with activity of eIF2 kinases. |
format | Online Article Text |
id | pubmed-5861040 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-58610402018-03-26 Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation Machado, Fabricio Castro Franco, Caio Haddad dos Santos Neto, Jose Vitorino Dias-Teixeira, Karina Luiza Moraes, Carolina Borsoi Lopes, Ulisses Gazos Aktas, Bertal Huseyin Schenkman, Sergio Sci Rep Article Some 1,3-diarylureas and 1-((1,4-trans)−4-aryloxycyclohexyl)−3-arylureas (cHAUs) activate heme-regulated kinase causing protein synthesis inhibition via phosphorylation of the eukaryotic translation initiation factor 2 (eIF2) in mammalian cancer cells. To evaluate if these agents have potential to inhibit trypanosome multiplication by also affecting the phosphorylation of eIF2 alpha subunit (eIF2α), we tested 25 analogs of 1,3-diarylureas and cHAUs against Trypanosoma cruzi, the agent of Chagas disease. One of them (I-17) presented selectivity close to 10-fold against the insect replicative forms and also inhibited the multiplication of T. cruzi inside mammalian cells with an EC(50) of 1–3 µM and a selectivity of 17-fold. I-17 also prevented replication of African trypanosomes (Trypanosoma brucei bloodstream and procyclic forms) at similar doses. It caused changes in the T. cruzi morphology, arrested parasite cell cycle in G1 phase, and promoted phosphorylation of eIF2α with a robust decrease in ribosome association with mRNA. The activity against T. brucei also implicates eIF2α phosphorylation, as replacement of WT-eIF2α with a non-phosphorylatable eIF2α, or knocking down eIF2 protein kinase-3 by RNAi increased resistance to I-17. Therefore, we demonstrate that eIF2α phosphorylation can be engaged to develop trypanosome-static agents in general, and particularly by interfering with activity of eIF2 kinases. Nature Publishing Group UK 2018-03-20 /pmc/articles/PMC5861040/ /pubmed/29559670 http://dx.doi.org/10.1038/s41598-018-23259-9 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Machado, Fabricio Castro Franco, Caio Haddad dos Santos Neto, Jose Vitorino Dias-Teixeira, Karina Luiza Moraes, Carolina Borsoi Lopes, Ulisses Gazos Aktas, Bertal Huseyin Schenkman, Sergio Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation |
title | Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation |
title_full | Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation |
title_fullStr | Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation |
title_full_unstemmed | Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation |
title_short | Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation |
title_sort | identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861040/ https://www.ncbi.nlm.nih.gov/pubmed/29559670 http://dx.doi.org/10.1038/s41598-018-23259-9 |
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