Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/30009
Title: Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni.
Authors: Marek, Martin
Kannan, Srinivasaraghavan
Hauser, Alexander-Thomas
Mourão, Marina Moraes
Caby, Stéphanie
Cura, Vincent
Stolfa, Diana A.
Schmidtkunz, Karin
Lancelot, Julien
ndrade, Luiza A
Renaud, Jean-Paul
Oliveira, Guilherme Correa de
Sippl, Wolfgang
Jung, Manfred
Cavarelli, Jean
Pierce, Raymond J.
Romier, Christophe
Affilliation: Département de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire.Université de Strasbourg. Illkirch, France
Institut für Pharmazie. Martin-Luther-Universität Halle-Wittenberg. Halle, Germany
Institut für Pharmazeutische Wissenschaften. Albert-Ludwigs-Universität Freiburg. Freiburg, Germany
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
Center for Infection and Immunity of Lille. Université Lille Nord de France. Institut Pasteur de Lille. Lille, France
Département de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire. Université de Strasbourg. Illkirch, France
Institut für Pharmazeutische Wissenschaften. Albert-Ludwigs-Universität Freiburg. Freiburg, Germany
Institut für Pharmazeutische Wissenschaften. Albert-Ludwigs-Universität Freiburg. Freiburg, Germany
Center for Infection and Immunity of Lille. Université Lille Nord de France. Institut Pasteur de Lille. Lille, France
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
Département de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire. Université de Strasbourg. Illkirch, France
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
Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany, Freiburg Institute of Advanced Studies (FRIAS), Albert-Ludwigs-Universität Freiburg, Freiburg, Germany
Institut für Pharmazeutische Wissenschaften. Albert-Ludwigs-Universität Freiburg. Freiburg, Germany/Freiburg Institute of Advanced Studies. Albert-Ludwigs-Universität Freiburg. Freiburg, Germany
Département de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire. Université de Strasbourg. Illkirch, France
Center for Infection and Immunity of Lille. Université Lille Nord de France. Institut Pasteur de Lille. Lille, France
Département de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire. Université de Strasbourg. Illkirch, France
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
Keywords: Schistosoma
Parasitic diseases
Schistosoma mansoni
Enzyme structure
phenylalanine
Zinc
Enzyme inhibitors
Epigenetics
keywords: Esquistossomosse
doenças parasitárias
Schistosoma mansoni
Issue Date: 2013
Publisher: Public Library of Science
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
DOI: 10.1371/journal.ppat.1003645
ISSN: 1553-7366
Copyright: open access
Appears in Collections:MG - IRR - Artigos de Periódicos

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