The antischistosomal potential of GSK-J4, an H3K27 demethylase inhibitor: insights from molecular modeling, transcriptomics and in vitro assays
Abstract 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...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-03-01
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| Series: | Parasites & Vectors |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13071-020-4000-z |
| _version_ | 1819114554653671424 |
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| author | Jessica Lobo-Silva Fernanda J. Cabral Murilo S. Amaral Patrícia A. Miyasato Rafaela Paula de Freitas Adriana S. A. Pereira Mariana I. Khouri Mayra M. F. Barbosa Pablo I. P. Ramos Luciana C. C. Leite Oluwatoyin A. Asojo Eliana Nakano Sergio Verjovski-Almeida Leonardo P. Farias |
| author_facet | Jessica Lobo-Silva Fernanda J. Cabral Murilo S. Amaral Patrícia A. Miyasato Rafaela Paula de Freitas Adriana S. A. Pereira Mariana I. Khouri Mayra M. F. Barbosa Pablo I. P. Ramos Luciana C. C. Leite Oluwatoyin A. Asojo Eliana Nakano Sergio Verjovski-Almeida Leonardo P. Farias |
| author_sort | Jessica Lobo-Silva |
| collection | DOAJ |
| description | Abstract 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 demethylases also seem to be important in the transition of cercariae into schistosomula, as well as sexual differentiation 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 profile of Smp_03400 was re-analyzed using available databases. The effect 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 fiber 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 identified 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 effects 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 fibers 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. |
| first_indexed | 2024-12-22T04:47:09Z |
| format | Article |
| id | doaj.art-b28fc045da46440890e0a7293e0916e7 |
| institution | Directory Open Access Journal |
| issn | 1756-3305 |
| language | English |
| last_indexed | 2024-12-22T04:47:09Z |
| publishDate | 2020-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Parasites & Vectors |
| spelling | doaj.art-b28fc045da46440890e0a7293e0916e72022-12-21T18:38:34ZengBMCParasites & Vectors1756-33052020-03-0113111610.1186/s13071-020-4000-zThe antischistosomal potential of GSK-J4, an H3K27 demethylase inhibitor: insights from molecular modeling, transcriptomics and in vitro assaysJessica Lobo-Silva0Fernanda J. Cabral1Murilo S. Amaral2Patrícia A. Miyasato3Rafaela Paula de Freitas4Adriana S. A. Pereira5Mariana I. Khouri6Mayra M. F. Barbosa7Pablo I. P. Ramos8Luciana C. C. Leite9Oluwatoyin A. Asojo10Eliana Nakano11Sergio Verjovski-Almeida12Leonardo P. Farias13Laboratório de Biomarcadores e Inflamação, Instituto Gonçalo Moniz, Fundação Oswaldo CruzDepartamento de Biologia Animal, Instituto de Biologia, Universidade Estadual de CampinasLaboratório de Expressão Gênica em Eucariotos, Instituto ButantanLaboratório de Parasitologia, Instituto ButantanLaboratório de Parasitologia, Instituto ButantanLaboratório de Expressão Gênica em Eucariotos, Instituto ButantanLaboratório de Biomarcadores e Inflamação, Instituto Gonçalo Moniz, Fundação Oswaldo CruzLaboratório Especial de Desenvolvimento de Vacinas, Instituto ButantanCentro de Integração de Dados e Conhecimentos para Saúde (CIDACS), Instituto Gonçalo Moniz, Fundação Oswaldo CruzLaboratório Especial de Desenvolvimento de Vacinas, Instituto ButantanDepartment of Chemistry and Biochemistry, Hampton UniversityLaboratório de Parasitologia, Instituto ButantanLaboratório de Expressão Gênica em Eucariotos, Instituto ButantanLaboratório de Biomarcadores e Inflamação, Instituto Gonçalo Moniz, Fundação Oswaldo CruzAbstract 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 demethylases also seem to be important in the transition of cercariae into schistosomula, as well as sexual differentiation 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 profile of Smp_03400 was re-analyzed using available databases. The effect 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 fiber 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 identified 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 effects 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 fibers 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.http://link.springer.com/article/10.1186/s13071-020-4000-zAnthelmintic drug discoveryEpigeneticsJumonji histone demethylase |
| spellingShingle | Jessica Lobo-Silva Fernanda J. Cabral Murilo S. Amaral Patrícia A. Miyasato Rafaela Paula de Freitas Adriana S. A. Pereira Mariana I. Khouri Mayra M. F. Barbosa Pablo I. P. Ramos Luciana C. C. Leite Oluwatoyin A. Asojo Eliana Nakano Sergio Verjovski-Almeida Leonardo P. Farias The antischistosomal potential of GSK-J4, an H3K27 demethylase inhibitor: insights from molecular modeling, transcriptomics and in vitro assays Parasites & Vectors Anthelmintic drug discovery Epigenetics Jumonji histone demethylase |
| title | 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_short | The antischistosomal potential of GSK-J4, an H3K27 demethylase inhibitor: insights from molecular modeling, transcriptomics and in vitro assays |
| title_sort | antischistosomal potential of gsk j4 an h3k27 demethylase inhibitor insights from molecular modeling transcriptomics and in vitro assays |
| topic | Anthelmintic drug discovery Epigenetics Jumonji histone demethylase |
| url | http://link.springer.com/article/10.1186/s13071-020-4000-z |
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