| Author | Marek, Martin | |
| Author | Kannan, Srinivasaraghavan | |
| Author | Hauser, Alexander-Thomas | |
| Author | Mourão, Marina Moraes | |
| Author | Caby, Stéphanie | |
| Author | Cura, Vincent | |
| Author | Stolfa, Diana A. | |
| Author | Schmidtkunz, Karin | |
| Author | Lancelot, Julien | |
| Author | Andrade, Luiza A | |
| Author | Renaud, Jean-Paul | |
| Author | Oliveira, Guilherme Correa de | |
| Author | Sippl, Wolfgang | |
| Author | Jung, Manfred | |
| Author | Cavarelli, Jean | |
| Author | Pierce, Raymond John | |
| Author | Romier, Christophe | |
| Access date | 2018-11-13T12:45:56Z | |
| Available date | 2018-11-13T12:45:56Z | |
| Document date | 2013 | |
| Citation | MAREK, Martin et al. Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni. PLoS Pathog., v. 9n. 9, e1003645, 2013 | pt_BR |
| ISSN | 1553-7366 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/30009 | |
| Language | eng | pt_BR |
| Publisher | Public Library of Science | pt_BR |
| Rights | open access | pt_BR |
| Subject in Portuguese | Esquistossomosse | pt_BR |
| Subject in Portuguese | doenças parasitárias | pt_BR |
| Subject in Portuguese | Schistosoma mansoni | pt_BR |
| Title | Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni. | pt_BR |
| Type | Article | pt_BR |
| DOI | 10.1371/journal.ppat.1003645 | |
| Abstract | The treatment of schistosomiasis, a disease caused by blood flukes parasites of the Schistosoma genus, depends on the intensive use of a single drug, praziquantel, which increases the likelihood of the development of drug-resistant parasite strains and renders the search for new drugs a strategic priority. Currently, inhibitors of human epigenetic enzymes are actively investigated as novel anti-cancer drugs and have the potential to be used as new anti-parasitic agents. Here, we report that Schistosoma mansoni histone deacetylase 8 (smHDAC8), the most expressed class I HDAC isotype in this organism, is a functional acetyl-L-lysine deacetylase that plays an important role in parasite infectivity. The crystal structure of smHDAC8 shows that this enzyme adopts a canonical α/β HDAC fold, with specific solvent exposed loops corresponding to insertions in the schistosome HDAC8 sequence. Importantly, structures of smHDAC8 in complex with generic HDAC inhibitors revealed specific structural changes in the smHDAC8 active site that cannot be accommodated by human HDACs. Using a structure-based approach, we identified several small-molecule inhibitors that build on these specificities. These molecules exhibit an inhibitory effect on smHDAC8 but show reduced affinity for human HDACs. Crucially, we show that a newly identified smHDAC8 inhibitor has the capacity to induce apoptosis and mortality in schistosomes. Taken together, our biological and structural findings define the framework for the rational design of small-molecule inhibitors specifically interfering with schistosome epigenetic mechanisms, and further support an anti-parasitic epigenome targeting strategy to treat neglected diseases caused by eukaryotic pathogens | pt_BR |
| Affilliation | Département de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire.Université de Strasbourg. Illkirch, France | pt_BR |
| Affilliation | Institut für Pharmazie. Martin-Luther-Universität Halle-Wittenberg. Halle, Germany | pt_BR |
| Affilliation | Institut für Pharmazeutische Wissenschaften. Albert-Ludwigs-Universität Freiburg. Freiburg, Germany | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais. Centro de Excelência em Bioinformática. Grupo de Genômica e Biologia Computacional. Belo Horizonte, MG, Brazil | pt_BR |
| Affilliation | Center for Infection and Immunity of Lille. Université Lille Nord de France. Institut Pasteur de Lille. Lille, France | pt_BR |
| Affilliation | Département de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire. Université de Strasbourg. Illkirch, France | pt_BR |
| Affilliation | Institut für Pharmazeutische Wissenschaften. Albert-Ludwigs-Universität Freiburg. Freiburg, Germany | pt_BR |
| Affilliation | Institut für Pharmazeutische Wissenschaften. Albert-Ludwigs-Universität Freiburg. Freiburg, Germany | pt_BR |
| Affilliation | Center for Infection and Immunity of Lille. Université Lille Nord de France. Institut Pasteur de Lille. Lille, France | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais. Centro de Excelência em Bioinformática. Grupo de Genômica e Biologia Computacional. Belo Horizonte, MG, Brazil | pt_BR |
| Affilliation | Département de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire. Université de Strasbourg. Illkirch, France | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais. Centro de Excelência em Bioinformática. Grupo de Genômica e Biologia Computacional. Belo Horizonte, MG, Brazil | pt_BR |
| Affilliation | Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany, Freiburg Institute of Advanced Studies (FRIAS), Albert-Ludwigs-Universität Freiburg, Freiburg, Germany | pt_BR |
| Affilliation | Institut für Pharmazeutische Wissenschaften. Albert-Ludwigs-Universität Freiburg. Freiburg, Germany/Freiburg Institute of Advanced Studies. Albert-Ludwigs-Universität Freiburg. Freiburg, Germany | pt_BR |
| Affilliation | Département de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire. Université de Strasbourg. Illkirch, France | pt_BR |
| Affilliation | Center for Infection and Immunity of Lille. Université Lille Nord de France. Institut Pasteur de Lille. Lille, France | pt_BR |
| Affilliation | Département de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire. Université de Strasbourg. Illkirch, France | pt_BR |
| Subject | Schistosoma | pt_BR |
| Subject | Parasitic diseases | pt_BR |
| Subject | Schistosoma mansoni | pt_BR |
| Subject | Enzyme structure | pt_BR |
| Subject | phenylalanine | pt_BR |
| Subject | Zinc | pt_BR |
| Subject | Enzyme inhibitors | pt_BR |
| Subject | Epigenetics | pt_BR |
| xmlui.metadata.dc.subject.ods | 03 Saúde e Bem-Estar | |
