The antischistosomal potential of GSK-J4, an H3K27 demethylase inhibitor: insights from molecular modeling, transcriptomics and in vitro assays
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2020 |
| Outros Autores: | , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Institucional da FIOCRUZ (ARCA) |
| Texto Completo: | https://www.arca.fiocruz.br/handle/icict/40763 |
Resumo: | Brazilian National Research Council (CNPq) (Grant number: 431155/2018-6) to LPF, the Fundação de Amparo a Pesquisa do Estado de São Paulo (Grant number: 2015/06366-2) to SVA and FJC 2017/07364-9. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brasil (CAPES) - Finance code 001. |
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Silva, Jessica LoboCabral, Fernanda J.Amaral, Murilo S.Miyasato, Patrícia A.Freitas, Rafaela Paula dePereira, Adriana S. A.Khouri, Mariana I.Barbosa, Mayra M. F.Ramos, Pablo I. P.Leite, Luciana C. C.Asojo, Oluwatoyin A.Nakano, ElianaAlmeida, Sergio VerjovskiFarias, Leonardo P.2020-04-15T13:19:39Z2020-04-15T13:19:39Z2020SILVA, Jessica Lobo et al. Antischistosomal potential of GSK-J4, an H3K27 demethylase inhibitor: insights from molecular modeling, transcriptomics and in vitro assays. Parasites Vectors, v. 13, p. 1-16, 2020.1756-3305https://www.arca.fiocruz.br/handle/icict/4076310.1186/s13071-020-4000-zBrazilian National Research Council (CNPq) (Grant number: 431155/2018-6) to LPF, the Fundação de Amparo a Pesquisa do Estado de São Paulo (Grant number: 2015/06366-2) to SVA and FJC 2017/07364-9. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brasil (CAPES) - Finance code 001.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Biomarcadores e Inflamação. Salvador, BA, Brasil.Universidade Estadual de Campinas. Instituto de Biologia. Departamento de Biologia Animal. Campinas, SP, Brasil.Instituto Butantan. Laboratório de Expressão Gênica em Eucariotos. São Paulo, SP, Brasil.Instituto Butantan. Laboratório de Parasitologia. São Paulo, SP, Brasil.Instituto Butantan. Laboratório de Parasitologia. São Paulo, SP, Brasil.Instituto Butantan. Laboratório de Expressão Gênica em Eucariotos. São Paulo, SP, Brasil / Universidade de São Paulo. Instituto de Química. Departamento de Bioquímica. São Paulo, SP, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Biomarcadores e Inflamação. Salvador, BA, Brasil.Instituto Butantan. Laboratório Especial de Desenvolvimento de Vacina. São Paulo, SP, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Centro de Integração de Dados e Conhecimentos para Saúde. Salvador, BA, Brasil.Instituto Butantan. Laboratório Especial de Desenvolvimento de Vacina. São Paulo, SP, Brasil.Hampton University. Department of Chemistry and Biochemistry, Hampton, VA, USA.Instituto Butantan. Laboratório de Parasitologia. São Paulo, SP, Brasil.Instituto Butantan. Laboratório de Expressão Gênica em Eucariotos. São Paulo, SP, Brasil / Universidade de São Paulo. Instituto de Química. Departamento de Bioquímica. São Paulo, SP, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Biomarcadores e Inflamação. Salvador, BA, Brasil.Background: Schistosomiasis chemotherapy is largely based on praziquantel (PZQ). Although PZQ is very safe and tolerable, it does not prevent reinfection and emerging resistance is a primary concern. Recent studies have shown that the targeting of epigenetic machinery in Schistosoma mansoni may result in severe alterations in parasite development, leading to death. This new route for drug discovery in schistosomiasis has focused on classes of histone deacetylases (HDACs) and histone acetyltransferases (HATs) as epigenetic drug targets. Schistosoma histone demethy‑lases also seem to be important in the transition of cercariae into schistosomula, as well as sexual diferentiation in adult worms. Methods: The Target-Pathogen database and molecular docking assays were used to prioritize the druggability of S. mansoni histone demethylases. The transcription profle of Smp_03400 was re-analyzed using available databases. The efect of GSK-J4 inhibitor in schistosomula and adult worms’ motility/viability/oviposition was assessed by in vitro assays. Ultrastructural analysis was performed on adult worms exposed to GSK-J4 by scanning electron microscopy, while internal structures and muscle fber integrity was investigated by confocal microscopy after Langeronʼs carmine or phalloidin staining. Results: The present evaluation of the potential druggability of 14 annotated S. mansoni demethylase enzymes identifed the S. mansoni ortholog of human KDM6A/UTX (Smp_034000) as the most suitable druggable target. In silico analysis and molecular modeling indicated the potential for cofactor displacement by the chemical probe GSK-J4. Our re-analysis of transcriptomic data revealed that Smp_034000 expression peaks at 24 h in newly transformed schistosomula and 5-week-old adult worms. Moreover, this gene was highly expressed in the testes of mature male worms compared to the rest of the parasite body. In in vitro schistosome cultures, treatment with GSK-J4 produced striking efects on schistosomula mortality and adult worm motility and mortality, as well as egg oviposition, in a dose- and time-dependent manner. Unexpectedly, western blot assays did not demonstrate overall modulation of H3K27me3 levels in response to GSK-J4. Confocal and scanning electron microscopy revealed the loss of original features in muscle fbers and alterations in cell-cell contact following GSK-J4 treatment. Conclusions: GSK-J4 presents promising potential for antischistosomal control; however, the underlying mechanisms warrant further investigation.engBMCDrogas anti-helmínticasEpigenéticaJumonji histona desmetilaseAnthelmintic drug discoveryEpigeneticsJumonji histone demethylaseThe antischistosomal potential of GSK-J4, an H3K27 demethylase inhibitor: insights from molecular modeling, transcriptomics and in vitro assaysinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/40763/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALSilva JL The antischistosomal...pdfSilva JL The 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14:34:21.226oai:www.arca.fiocruz.br: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ório 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| dc.title.pt_BR.fl_str_mv |
The antischistosomal potential of GSK-J4, an H3K27 demethylase inhibitor: insights from molecular modeling, transcriptomics and in vitro assays |
| title |
The antischistosomal potential of GSK-J4, an H3K27 demethylase inhibitor: insights from molecular modeling, transcriptomics and in vitro assays |
| spellingShingle |
The antischistosomal potential of GSK-J4, an H3K27 demethylase inhibitor: insights from molecular modeling, transcriptomics and in vitro assays Silva, Jessica Lobo Drogas anti-helmínticas Epigenética Jumonji histona desmetilase Anthelmintic drug discovery Epigenetics Jumonji histone demethylase |
| title_short |
The antischistosomal potential of GSK-J4, an H3K27 demethylase inhibitor: insights from molecular modeling, transcriptomics and in vitro assays |
| title_full |
The antischistosomal potential of GSK-J4, an H3K27 demethylase inhibitor: insights from molecular modeling, transcriptomics and in vitro assays |
| title_fullStr |
The antischistosomal potential of GSK-J4, an H3K27 demethylase inhibitor: insights from molecular modeling, transcriptomics and in vitro assays |
| title_full_unstemmed |
The antischistosomal potential of GSK-J4, an H3K27 demethylase inhibitor: insights from molecular modeling, transcriptomics and in vitro assays |
| title_sort |
The antischistosomal potential of GSK-J4, an H3K27 demethylase inhibitor: insights from molecular modeling, transcriptomics and in vitro assays |
| author |
Silva, Jessica Lobo |
| author_facet |
Silva, Jessica Lobo Cabral, Fernanda J. Amaral, Murilo S. Miyasato, Patrícia A. Freitas, Rafaela Paula de Pereira, Adriana S. A. Khouri, Mariana I. Barbosa, Mayra M. F. Ramos, Pablo I. P. Leite, Luciana C. C. Asojo, Oluwatoyin A. Nakano, Eliana Almeida, Sergio Verjovski Farias, Leonardo P. |
| author_role |
author |
| author2 |
Cabral, Fernanda J. Amaral, Murilo S. Miyasato, Patrícia A. Freitas, Rafaela Paula de Pereira, Adriana S. A. Khouri, Mariana I. Barbosa, Mayra M. F. Ramos, Pablo I. P. Leite, Luciana C. C. Asojo, Oluwatoyin A. Nakano, Eliana Almeida, Sergio Verjovski Farias, Leonardo P. |
| author2_role |
author author author author author author author author author author author author author |
| dc.contributor.author.fl_str_mv |
Silva, Jessica Lobo Cabral, Fernanda J. Amaral, Murilo S. Miyasato, Patrícia A. Freitas, Rafaela Paula de Pereira, Adriana S. A. Khouri, Mariana I. Barbosa, Mayra M. F. Ramos, Pablo I. P. Leite, Luciana C. C. Asojo, Oluwatoyin A. Nakano, Eliana Almeida, Sergio Verjovski Farias, Leonardo P. |
| dc.subject.other.pt_BR.fl_str_mv |
Drogas anti-helmínticas Epigenética Jumonji histona desmetilase |
| topic |
Drogas anti-helmínticas Epigenética Jumonji histona desmetilase Anthelmintic drug discovery Epigenetics Jumonji histone demethylase |
| dc.subject.en.pt_BR.fl_str_mv |
Anthelmintic drug discovery Epigenetics Jumonji histone demethylase |
| description |
Brazilian National Research Council (CNPq) (Grant number: 431155/2018-6) to LPF, the Fundação de Amparo a Pesquisa do Estado de São Paulo (Grant number: 2015/06366-2) to SVA and FJC 2017/07364-9. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brasil (CAPES) - Finance code 001. |
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2020 |
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2020-04-15T13:19:39Z |
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2020-04-15T13:19:39Z |
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2020 |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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SILVA, Jessica Lobo et al. Antischistosomal potential of GSK-J4, an H3K27 demethylase inhibitor: insights from molecular modeling, transcriptomics and in vitro assays. Parasites Vectors, v. 13, p. 1-16, 2020. |
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https://www.arca.fiocruz.br/handle/icict/40763 |
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1756-3305 |
| dc.identifier.doi.none.fl_str_mv |
10.1186/s13071-020-4000-z |
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SILVA, Jessica Lobo et al. Antischistosomal potential of GSK-J4, an H3K27 demethylase inhibitor: insights from molecular modeling, transcriptomics and in vitro assays. Parasites Vectors, v. 13, p. 1-16, 2020. 1756-3305 10.1186/s13071-020-4000-z |
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