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

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dc.citation.volumev. 8
dc.contributor.authorMachado, Fabricio Castro [UNIFESP]
dc.contributor.authorFranco, Caio Haddad [UNIFESP]
dc.contributor.authorSantos Neto, Jose Vitorino dos
dc.contributor.authorDias-Teixeira, Karina Luiza
dc.contributor.authorMoraes, Carolina Borsoi
dc.contributor.authorLopes, Ulisses Gazos
dc.contributor.authorAktas, Bertal Huseyin
dc.contributor.authorSchenkman, Sergio [UNIFESP]
dc.coverageLondon
dc.date.accessioned2020-07-20T16:31:14Z
dc.date.available2020-07-20T16:31:14Z
dc.date.issued2018
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.en
dc.description.affiliationUniv Fed Sao Paulo, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, BR-04039032 Sao Paulo, SP, Brazil
dc.description.affiliationUniv Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Lab Parasitol Mol, Rio De Janeiro, RJ, Brazil
dc.description.affiliationInst Butantan, Sao Paulo, SP, Brazil
dc.description.affiliationUniv Sao Paulo, Inst Ciencias Biomed, Dept Microbiol, Sao Paulo, SP, Brazil
dc.description.affiliationBrigham & Womens Hosp, Dept Med, Hematol Lab Translat Res, 75 Francis St, Boston, MA 02115 USA
dc.description.affiliationHarvard Med Sch, 75 Francis St, Boston, MA 02115 USA
dc.description.affiliationUnifespUniv Fed Sao Paulo, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, BR-04039032 Sao Paulo, SP, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)
dc.description.sponsorshipCNPq
dc.description.sponsorshipFundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ)
dc.description.sponsorshipNIH
dc.description.sponsorshipIDFAPESP: 2015/20031-0
dc.description.sponsorshipIDFAPESP: 2014/01577-2
dc.description.sponsorshipIDCNPq: 445655/2014-3
dc.description.sponsorshipIDNIH: R01 CA152312
dc.format.extent-
dc.identifierhttp://dx.doi.org/10.1038/s41598-018-23259-9
dc.identifier.citationScientific Reports. London, v. 8, 2018.
dc.identifier.doi10.1038/s41598-018-23259-9
dc.identifier.fileWOS000427819900002.pdf
dc.identifier.issn2045-2322
dc.identifier.urihttps://repositorio.unifesp.br/handle/11600/55808
dc.identifier.wosWOS:000427819900002
dc.language.isoeng
dc.publisherNature Publishing Group
dc.relation.ispartofScientific Reports
dc.rightsinfo:eu-repo/semantics/openAccess
dc.titleIdentification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiationen
dc.typeinfo:eu-repo/semantics/article
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