Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni.

Submitted by Nuzia Santos ([email protected]) on 2018-11-13T12:09:19Z No. of bitstreams: 1 Structural Basis for the Inhibition of Histone .pdf: 10051721 bytes, checksum: 36ced7239c061ef58937ef2728effa22 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2018-11-13T12:45:56Z (GMT) No. of bitstreams: 1 Structural Basis for the Inhibition of Histone .pdf: 10051721 bytes, checksum: 36ced7239c061ef58937ef2728effa22 (MD5)Made available in DSpace on 2018-11-13T12:45:56Z (GMT). No. of bitstreams: 1 Structural Basis for the Inhibition of Histone .pdf: 10051721 bytes, checksum: 36ced7239c061ef58937ef2728effa22 (MD5) Previous issue date: 2013Département de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire.Université de Strasbourg. Illkirch, FranceInstitut für Pharmazie. Martin-Luther-Universität Halle-Wittenberg. Halle, GermanyInstitut für Pharmazeutische Wissenschaften. Albert-Ludwigs-Universität Freiburg. Freiburg, GermanyFundação 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, BrazilCenter for Infection and Immunity of Lille. Université Lille Nord de France. Institut Pasteur de Lille. Lille, FranceDépartement de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire. Université de Strasbourg. Illkirch, FranceInstitut für Pharmazeutische Wissenschaften. Albert-Ludwigs-Universität Freiburg. Freiburg, GermanyInstitut für Pharmazeutische Wissenschaften. Albert-Ludwigs-Universität Freiburg. Freiburg, GermanyCenter for Infection and Immunity of Lille. Université Lille Nord de France. Institut Pasteur de Lille. Lille, FranceFundação 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, BrazilDépartement de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire. Université de Strasbourg. Illkirch, FranceFundação 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, BrazilInstitut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany, Freiburg Institute of Advanced Studies (FRIAS), Albert-Ludwigs-Universität Freiburg, Freiburg, GermanyInstitut für Pharmazeutische Wissenschaften. Albert-Ludwigs-Universität Freiburg. Freiburg, Germany/Freiburg Institute of Advanced Studies. Albert-Ludwigs-Universität Freiburg. Freiburg, GermanyDépartement de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire. Université de Strasbourg. Illkirch, FranceCenter for Infection and Immunity of Lille. Université Lille Nord de France. Institut Pasteur de Lille. Lille, FranceDépartement de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire. Université de Strasbourg. Illkirch, FranceThe 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 pathogen