title: Molecular basis for the antiparasitic activity of a mercaptoacetamide derivative that inhibits histone deacetylase 8 (HDAC8) from the human pathogen schistosoma mansoni.
abstract: Schistosomiasis, caused by the parasitic flatworm Schistosoma mansoni and related species, is a tropical disease that affects over 200 million people worldwide. A new approach for targeting eukaryotic parasites is to tackle their dynamic epigenetic machinery that is necessary for the extensive phenotypic changes during the life cycle of the parasite. Recently, we identified S. mansoni histone deacetylase 8 (smHDAC8) as a potential target for antiparasitic therapy. Here, we present results on the investigations of a focused set of HDAC (histone deacetylase) inhibitors on smHDAC8. Besides several active hydroxamates, we identified a thiol-based inhibitor that inhibited smHDAC8 activity in the micromolar range with unexpected selectivity over the human isotype, which has not been observed so far. The crystal structure of smHDAC8 complexed with the thiol derivative revealed that the inhibitor is accommodated in the catalytic pocket, where it interacts with both the catalytic zinc ion and the essential catalytic tyrosine (Y341) residue via its mercaptoacetamide warhead. To our knowledge, this is the first complex crystal structure of any HDAC inhibited by a mercaptoacetamide inhibitor, and therefore, this finding offers a rationale for further improvement. Finally, an ester prodrug of the thiol HDAC inhibitor exhibited antiparasitic activity on cultured schistosomes in a dose-dependent manner.
authors.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstraße 25, 79104 Freiburg, Germany.
authors.forename: Diana A
authors.initials: DA
authors.lastname: Stolfa
authors.affiliation: Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire, Université de Strasbourg, CNRS, INSERM, 1 rue Laurent Fries, BP 10142, 67404 Illkirch Cedex, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Marek
authors.affiliation: Center for Infection and Immunity of Lille, INSERM U1019-CNRS UMR 8204, Université Lille Nord de France, Institut Pasteur de Lille, 1 rue Professeur Calmette, F-59019 Lille Cedex, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Lancelot
authors.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstraße 25, 79104 Freiburg, Germany.
authors.forename: Alexander-Thomas
authors.initials: AT
authors.lastname: Hauser
authors.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstraße 25, 79104 Freiburg, Germany; German Cancer Consortium (DKTK), Freiburg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Walter
authors.affiliation: Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire, Université de Strasbourg, CNRS, INSERM, 1 rue Laurent Fries, BP 10142, 67404 Illkirch Cedex, France.
authors.forename: Emeline
authors.initials: E
authors.lastname: Leproult
authors.affiliation: Institute of Pharmacy, Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Straße 4, 06120 Halle/Saale, Germany.
authors.forename: Jelena
authors.initials: J
authors.lastname: Melesina
authors.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstraße 25, 79104 Freiburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Rumpf
authors.affiliation: Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire, Université de Strasbourg, CNRS, INSERM, 1 rue Laurent Fries, BP 10142, 67404 Illkirch Cedex, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Wurtz
authors.affiliation: Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire, Université de Strasbourg, CNRS, INSERM, 1 rue Laurent Fries, BP 10142, 67404 Illkirch Cedex, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Cavarelli
authors.affiliation: Institute of Pharmacy, Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Straße 4, 06120 Halle/Saale, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
authors.affiliation: Center for Infection and Immunity of Lille, INSERM U1019-CNRS UMR 8204, Université Lille Nord de France, Institut Pasteur de Lille, 1 rue Professeur Calmette, F-59019 Lille Cedex, France.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Pierce
authors.affiliation: Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire, Université de Strasbourg, CNRS, INSERM, 1 rue Laurent Fries, BP 10142, 67404 Illkirch Cedex, France. Electronic address: romier@igbmc.fr.
authors.forename: Christophe
authors.initials: C
authors.lastname: Romier
authors.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstraße 25, 79104 Freiburg, Germany. Electronic address: manfred.jung@pharmazie.uni-freiburg.de.
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D055162:Biocatalysis / Q000187:drug effects; D018360:Crystallography, X-Ray; D015801:Helminth Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012550:Schistosoma mansoni / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D012555:Schistosomiasis mansoni / Q000469:parasitology; D013853:Thioacetamide / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000077337:Vorinostat
chemical_list: D000977:Antiparasitic Agents; D015801:Helminth Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013853:Thioacetamide; D000077337:Vorinostat; D006655:Histone Deacetylases
keywords: X-ray crystallography; antiparasitic activity; docking; epigenetics; thiol