Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni

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dc.contributorLaboratório de Parasitologiapt_BR
dc.contributor.authorCarneiro, Vitor Coutinhopt_BR
dc.contributor.authorSilva, Isabel Caetano de Abreu dapt_BR
dc.contributor.authorAmaral, Murilo Senapt_BR
dc.contributor.authorPereira, Adriana da Silva Andradept_BR
dc.contributor.authorSilveira, Gilbert de Oliveirapt_BR
dc.contributor.authorPires, David da Silvapt_BR
dc.contributor.authorVerjovski-Almeida, Sergiopt_BR
dc.contributor.authorDekker, Frank J.pt_BR
dc.contributor.authorRotili, Dantept_BR
dc.contributor.authorMai, Antonellopt_BR
dc.contributor.authorLopes-Torres, Eduardo Josépt_BR
dc.contributor.authorRobaa, Dinapt_BR
dc.contributor.authorSippl, Wolfgangpt_BR
dc.contributor.authorPierce, Raymond J.pt_BR
dc.contributor.authorBorrello, M. Teresapt_BR
dc.contributor.authorGanesan, A.pt_BR
dc.contributor.authorLancelot, Julienpt_BR
dc.contributor.authorThiengo, Silvanapt_BR
dc.contributor.authorFernandez, Monica Ammonpt_BR
dc.contributor.authorVicentino, Amanda Roberta Revoredopt_BR
dc.contributor.authorMourão, Marina Moraespt_BR
dc.contributor.authorCoelho, Fernanda Salespt_BR
dc.contributor.authorFantappié, Marcelo Rosadopt_BR
dc.date.accessioned2020-07-29T17:44:31Z-
dc.date.available2020-07-29T17:44:31Z-
dc.date.issued2020-
dc.identifier.citationCarneiro VC, Silva ICA, Amaral MS, Pereira ASA, Silveira GO, Pires DS, et al. Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni. Plos Negl. Trop. Dis.. 2020 Jul;14(7):e0008332. doi:10.1371/journal.pntd.0008332.pt_BR
dc.identifier.issn1935-2735-
dc.identifier.issn1935-2727-
dc.identifier.urihttps://repositorio.butantan.gov.br/handle/butantan/3085-
dc.description.abstractTreatment and control of schistosomiasis still rely on only one effective drug, praziquantel (PZQ) and, due to mass treatment, the increasing risk of selecting for schistosome strains that are resistant to PZQ has alerted investigators to the urgent need to develop novel therapeutic strategies. The histone-modifying enzymes (HMEs) represent promising targets for the development of epigenetic drugs against Schistosoma mansoni. In the present study, we targeted the S. mansoni lysine-specific demethylase 1 (SmLSD1), a transcriptional corepressor, using a novel and selective synthetic inhibitor, MC3935, which was used to treat schistosomula and adult worms in vitro. By using cell viability assays and optical and electron microscopy, we showed that treatment with MC3935 affected parasite motility, egg-laying, tegument, and cellular organelle structures, culminating in the death of schistosomula and adult worms. In silico molecular modeling and docking analysis suggested that MC3935 binds to the catalytic pocket of SmLSD1. Western blot analysis revealed that MC3935 inhibited SmLSD1 demethylation activity of H3K4me1/2. Knockdown of SmLSD1 by RNAi recapitulated MC3935 phenotypes in adult worms. RNA-Seq analysis of MC3935-treated parasites revealed significant differences in gene expression related to critical biological processes. Collectively, our findings show that SmLSD1 is a promising drug target for the treatment of schistosomiasis and strongly support the further development and in vivo testing of selective schistosome LSD1 inhibitors.pt_BR
dc.description.sponsorshipEuropean Union’s Seventh Framework Programmept_BR
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)pt_BR
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)pt_BR
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)pt_BR
dc.description.sponsorshipEuropean Regional Development Fund (ERDF)pt_BR
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)pt_BR
dc.format.extente0008332pt_BR
dc.languageengpt_BR
dc.publisherPublic Library of Sciencept_BR
dc.relation.ispartofPlos Neglected Tropical Diseasespt_BR
dc.rightsOpen Accesspt_BR
dc.titlePharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansonipt_BR
dc.typeArticlept_BR
dc.identifier.doi10.1371/journal.pntd.0008332pt_BR
dc.identifier.urlhttps://doi.org/10.1371/journal.pntd.0008332pt_BR
dc.contributor.externalGerman Cancer Research Centerpt_BR
dc.contributor.externalUniversidade Federal do Rio de Janeiro (UFRJ)pt_BR
dc.contributor.externalUniversidade de São Paulo (USP)pt_BR
dc.contributor.externalUniversity of Groningenpt_BR
dc.contributor.externalSapienza University of Romept_BR
dc.contributor.externalUniversidade do Estado do Rio de Janeiro (UERJ)pt_BR
dc.contributor.externalMartin Luther University Halle-Wittenberg (MLU)pt_BR
dc.contributor.externalUniversité de Lillept_BR
dc.contributor.externalInstitut Pasteur de Lillept_BR
dc.contributor.externalCentre de Recherche en Cancérologie de Marseille (CRCM)pt_BR
dc.contributor.externalAix-Marseille Universitépt_BR
dc.contributor.externalUniversity of East Anglia (UEA)pt_BR
dc.contributor.externalFundação Oswaldo Cruz (Fiocruz)pt_BR
dc.contributor.externalInstituto Oswaldo Cruz (IOC)pt_BR
dc.contributor.externalInstituto René Rachou (Fiocruz Minas)pt_BR
dc.publisher.citySan Franciscopt_BR
dc.identifier.citationvolume14pt_BR
dc.identifier.citationissue7pt_BR
dc.relation.ispartofabbreviatedPlos Negl. Trop. Dis.pt_BR
dc.identifier.citationabntv. 14, n. 7, e0008332, jul. 2020pt_BR
dc.identifier.citationvancouver2020 Jul;14(7):e0008332pt_BR
dc.publisher.countryUnited Statespt_BR
dc.contributor.butantanAmaral, Murilo Sena|:Técnico|:Laboratório de Parasitologiapt_BR
dc.contributor.butantanPereira, Adriana da Silva Andrade|:Aluno|:Laboratório de Parasitologiapt_BR
dc.contributor.butantanSilveira, Gilbert de Oliveira|:Aluno|:Laboratório de Parasitologiapt_BR
dc.contributor.butantanPires, David da Silva|:Técnico|:Laboratório de Parasitologiapt_BR
dc.contributor.butantanVerjovski-Almeida, Sergio|:Pesquisador|:Laboratório de Parasitologiapt_BR
dc.sponsorship.butantanEuropean Union’s Seventh Framework Programme¦¦602080pt_BR
dc.sponsorship.butantanCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)pt_BR
dc.sponsorship.butantanConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)pt_BR
dc.sponsorship.butantanFundacao de Amparo Pesquisa do Estado de Sao Paulo (FAPESP)¦¦2018/24015-0pt_BR
dc.sponsorship.butantanEuropean Regional Development Fund (ERDF)pt_BR
dc.sponsorship.butantanFundação de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ)¦¦202.660/2018pt_BR
dc.identifier.bvsccBR78.1pt_BR
dc.identifier.bvsdbIBProdpt_BR
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