Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation

Full metadata record
DC FieldValueLanguage
dc.contributor.authorMachado, Fabricio Castropt_BR
dc.contributor.authorFranco, Caio Haddadpt_BR
dc.contributor.authordos Santos Neto, Jose Vitorinopt_BR
dc.contributor.authorDias-Teixeira, Karina Luizapt_BR
dc.contributor.authorMoraes, Carolina Borsoipt_BR
dc.contributor.authorLopes, Ulisses Gazospt_BR
dc.contributor.authorAktas, Bertal Huseyinpt_BR
dc.contributor.authorSchenkman, Sergiopt_BR
dc.date.accessioned2020-07-09T21:19:10Z-
dc.date.available2020-07-09T21:19:10Z-
dc.date.issued2018-
dc.identifier.citationMachado FC, Franco CH, dos Santos Neto JV, Dias-Teixeira KL, Moraes CB, Lopes UG, et al. Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation. Sci Rep. 2018 Mar;8:4857. doi:10.1038/s41598-018-23259-9.pt_BR
dc.identifier.urihttps://repositorio.butantan.gov.br/handle/butantan/2402-
dc.description.abstractSome 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.pt_BR
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)pt_BR
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)pt_BR
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)pt_BR
dc.description.sponsorshipNational Institutes of Health (NIH)pt_BR
dc.format.extent4857pt_BR
dc.languageengpt_BR
dc.relation.ispartofScientific Reportspt_BR
dc.rightsOpen Accesspt_BR
dc.titleIdentification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiationpt_BR
dc.typeArticlept_BR
dc.identifier.doi10.1038/s41598-018-23259-9pt_BR
dc.identifier.urlhttp://dx.doi.org/10.1038/s41598-018-23259-9pt_BR
dc.contributor.externalUniversidade Federal de São Paulo (UNIFESP)¦¦Brasilpt_BR
dc.contributor.externalUniversidade de São Paulo (USP)¦¦Brasilpt_BR
dc.contributor.externalUniversidade Federal do Rio de Janeiro (UFRJ)¦¦Brasilpt_BR
dc.contributor.externalBrigham and Women's Hospital (BHW)¦¦Estados Unidospt_BR
dc.contributor.externalHarvard University¦¦Estados Unidospt_BR
dc.identifier.citationvolume8pt_BR
dc.relation.ispartofabbreviatedSci Reppt_BR
dc.identifier.citationabntv. 8, 4857, mar. 2018pt_BR
dc.identifier.citationvancouver2018 Mar;8:4857pt_BR
dc.contributor.butantanFranco, Caio Haddad|:|:|:pt_BR
dc.contributor.butantanMoraes, Carolina Borsoi|:|:|:pt_BR
dc.sponsorship.butantanConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)¦¦445655/2014-3pt_BR
dc.sponsorship.butantanFundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)¦¦pt_BR
dc.sponsorship.butantanFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)¦¦2015/20031-0pt_BR
dc.sponsorship.butantanFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)¦¦2014/01577-2pt_BR
dc.sponsorship.butantanNational Institutes of Health (NIH)¦¦R01 CA152312pt_BR
dc.identifier.bvsccBR78.1pt_BR
dc.identifier.bvsdbIBProdpt_BR
item.openairetypeArticle-
item.fulltextCom Texto completo-
item.grantfulltextembargo_29990101-
crisitem.journal.journalissn#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.journal.journaleissn#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.dept#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.dept#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.dept#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.dept#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.dept#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.dept#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.dept#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.dept#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.orcid#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.orcid#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.orcid#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.orcid#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.orcid#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.orcid#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.orcid#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.orcid#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.parentorg#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.parentorg#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.parentorg#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.parentorg#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.parentorg#PLACEHOLDER_PARENT_METADATA_VALUE#-
crisitem.author.parentorg#PLACEHOLDER_PARENT_METADATA_VALUE#-
Appears in Collections:Artigos de periódicos

Files in This Item:
File SizeFormat Existing users please Login
10.1038:s41598-018-23259-9.pdf2.32 MBAdobe PDFEmbargoed until January 1, 2999    Request a copy
Show simple item record

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.