Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNIFESP |
Texto Completo: | https://repositorio.unifesp.br/handle/11600/55808 http://dx.doi.org/10.1038/s41598-018-23259-9 |
Resumo: | 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 (eIF2 alpha), 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 EC50 of 1-3 mu M 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 eIF2 alpha with a robust decrease in ribosome association with mRNA. The activity against T. brucei also implicates eIF2 alpha phosphorylation, as replacement of WT-eIF2 alpha with a non-phosphorylatable eIF2 alpha, or knocking down eIF2 protein kinase-3 by RNAi increased resistance to I-17. Therefore, we demonstrate that eIF2 alpha phosphorylation can be engaged to develop trypanosome-static agents in general, and particularly by interfering with activity of eIF2 kinases. |
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Machado, Fabricio Castro [UNIFESP]Franco, Caio Haddad [UNIFESP]Santos Neto, Jose Vitorino dosDias-Teixeira, Karina LuizaMoraes, Carolina BorsoiLopes, Ulisses GazosAktas, Bertal HuseyinSchenkman, Sergio [UNIFESP]2020-07-20T16:31:14Z2020-07-20T16:31:14Z2018Scientific Reports. London, v. 8, 2018.2045-2322https://repositorio.unifesp.br/handle/11600/55808http://dx.doi.org/10.1038/s41598-018-23259-9WOS000427819900002.pdf10.1038/s41598-018-23259-9WOS:000427819900002Some 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 (eIF2 alpha), 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 EC50 of 1-3 mu M 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 eIF2 alpha with a robust decrease in ribosome association with mRNA. The activity against T. brucei also implicates eIF2 alpha phosphorylation, as replacement of WT-eIF2 alpha with a non-phosphorylatable eIF2 alpha, or knocking down eIF2 protein kinase-3 by RNAi increased resistance to I-17. Therefore, we demonstrate that eIF2 alpha phosphorylation can be engaged to develop trypanosome-static agents in general, and particularly by interfering with activity of eIF2 kinases.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)CNPqFundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ)NIHUniv Fed Sao Paulo, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, BR-04039032 Sao Paulo, SP, BrazilUniv Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Lab Parasitol Mol, Rio De Janeiro, RJ, BrazilInst Butantan, Sao Paulo, SP, BrazilUniv Sao Paulo, Inst Ciencias Biomed, Dept Microbiol, Sao Paulo, SP, BrazilBrigham & Womens Hosp, Dept Med, Hematol Lab Translat Res, 75 Francis St, Boston, MA 02115 USAHarvard Med Sch, 75 Francis St, Boston, MA 02115 USAUniv Fed Sao Paulo, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, BR-04039032 Sao Paulo, SP, BrazilFAPESP: 2015/20031-0FAPESP: 2014/01577-2CNPq: 445655/2014-3NIH: R01 CA152312Web of Science-engNature Publishing GroupScientific ReportsIdentification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiationinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleLondonv. 8info:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESPORIGINALWOS000427819900002.pdfapplication/pdf2372038${dspace.ui.url}/bitstream/11600/55808/1/WOS000427819900002.pdf63455443b3c427fb1255abd9f3605defMD51open accessTEXTWOS000427819900002.pdf.txtWOS000427819900002.pdf.txtExtracted texttext/plain64297${dspace.ui.url}/bitstream/11600/55808/2/WOS000427819900002.pdf.txt815419cc39dd97f36f53350e8ce865bbMD52open accessTHUMBNAILWOS000427819900002.pdf.jpgWOS000427819900002.pdf.jpgIM Thumbnailimage/jpeg7514${dspace.ui.url}/bitstream/11600/55808/4/WOS000427819900002.pdf.jpg5da099f82d74bccb593dabb48c58cd11MD54open access11600/558082022-08-01 02:15:02.058open accessoai:repositorio.unifesp.br:11600/55808Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestopendoar:34652022-08-01T05:15:02Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false |
dc.title.en.fl_str_mv |
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 |
spellingShingle |
Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation Machado, Fabricio Castro [UNIFESP] |
title_short |
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_sort |
Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation |
author |
Machado, Fabricio Castro [UNIFESP] |
author_facet |
Machado, Fabricio Castro [UNIFESP] Franco, Caio Haddad [UNIFESP] Santos Neto, Jose Vitorino dos Dias-Teixeira, Karina Luiza Moraes, Carolina Borsoi Lopes, Ulisses Gazos Aktas, Bertal Huseyin Schenkman, Sergio [UNIFESP] |
author_role |
author |
author2 |
Franco, Caio Haddad [UNIFESP] Santos Neto, Jose Vitorino dos Dias-Teixeira, Karina Luiza Moraes, Carolina Borsoi Lopes, Ulisses Gazos Aktas, Bertal Huseyin Schenkman, Sergio [UNIFESP] |
author2_role |
author author author author author author author |
dc.contributor.author.fl_str_mv |
Machado, Fabricio Castro [UNIFESP] Franco, Caio Haddad [UNIFESP] Santos Neto, Jose Vitorino dos Dias-Teixeira, Karina Luiza Moraes, Carolina Borsoi Lopes, Ulisses Gazos Aktas, Bertal Huseyin Schenkman, Sergio [UNIFESP] |
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 (eIF2 alpha), 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 EC50 of 1-3 mu M 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 eIF2 alpha with a robust decrease in ribosome association with mRNA. The activity against T. brucei also implicates eIF2 alpha phosphorylation, as replacement of WT-eIF2 alpha with a non-phosphorylatable eIF2 alpha, or knocking down eIF2 protein kinase-3 by RNAi increased resistance to I-17. Therefore, we demonstrate that eIF2 alpha phosphorylation can be engaged to develop trypanosome-static agents in general, and particularly by interfering with activity of eIF2 kinases. |
publishDate |
2018 |
dc.date.issued.fl_str_mv |
2018 |
dc.date.accessioned.fl_str_mv |
2020-07-20T16:31:14Z |
dc.date.available.fl_str_mv |
2020-07-20T16:31:14Z |
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status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
Scientific Reports. London, v. 8, 2018. |
dc.identifier.uri.fl_str_mv |
https://repositorio.unifesp.br/handle/11600/55808 http://dx.doi.org/10.1038/s41598-018-23259-9 |
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2045-2322 |
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WOS000427819900002.pdf |
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10.1038/s41598-018-23259-9 |
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Scientific Reports. London, v. 8, 2018. 2045-2322 WOS000427819900002.pdf 10.1038/s41598-018-23259-9 WOS:000427819900002 |
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