title: Structure-Based Design and Synthesis of Novel Inhibitors Targeting HDAC8 from Schistosoma mansoni for the Treatment of Schistosomiasis.
abstract: Schistosomiasis is a major neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. In this study, a series of new benzohydroxamates were prepared as potent inhibitors of Schistosoma mansoni histone deacetylase 8 (smHDAC8). Crystallographic analysis provided insights into the inhibition mode of smHDAC8 activity by these 3-amidobenzohydroxamates. The newly designed inhibitors were evaluated in screens for enzyme inhibitory activity against schistosome and human HDACs. Twenty-seven compounds were found to be active in the nanomolar range, and some of them showed selectivity toward smHDAC8 over the major human HDACs (1 and 6). The active benzohydroxamates were additionally screened for lethality against the schistosome larval stage using a fluorescence-based assay. Four of these showed significant dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture.
authors.affiliation: Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg , 06120 Halle/Saale, Germany.
authors.forename: Tino
authors.initials: T
authors.lastname: Heimburg
authors.affiliation: Institute of Pharmaceutical Sciences, University of Freiburg , 79104 Freiburg, Germany.
authors.forename: Alokta
authors.initials: A
authors.lastname: Chakrabarti
authors.affiliation: Université de Lille, CNRS, Inserm , CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d'Infection et d'Immunité de Lille, 59000 Lille, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Lancelot
authors.affiliation: Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UDS), CNRS, INSERM , 67404 Illkirch Cedex, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Marek
authors.affiliation: Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg , 06120 Halle/Saale, Germany.
authors.forename: Jelena
authors.initials: J
authors.lastname: Melesina
authors.affiliation: Institute of Pharmaceutical Sciences, University of Freiburg , 79104 Freiburg, Germany.
authors.forename: Alexander-Thomas
authors.initials: AT
authors.lastname: Hauser
authors.affiliation: Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UDS), CNRS, INSERM , 67404 Illkirch Cedex, France.
authors.forename: Tajith B
authors.initials: TB
authors.lastname: Shaik
authors.affiliation: Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UDS), CNRS, INSERM , 67404 Illkirch Cedex, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Duclaud
authors.affiliation: Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg , 06120 Halle/Saale, Germany.
authors.forename: Dina
authors.initials: D
authors.lastname: Robaa
authors.affiliation: Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg , 06120 Halle/Saale, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Erdmann
authors.affiliation: Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg , 06120 Halle/Saale, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UDS), CNRS, INSERM , 67404 Illkirch Cedex, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Romier
authors.affiliation: Université de Lille, CNRS, Inserm , CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d'Infection et d'Immunité de Lille, 59000 Lille, France.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Pierce
authors.affiliation: Institute of Pharmaceutical Sciences, University of Freiburg , 79104 Freiburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
authors.affiliation: Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg , 06120 Halle/Saale, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D015801:Helminth Proteins / Q000187:drug effects*; D006655:Histone Deacetylases / Q000187:drug effects*; D006801:Humans; D007814:Larva; D008958:Models, Molecular; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000235:genetics; D012555:Schistosomiasis mansoni / Q000188:drug therapy; D012556:Schistosomicides / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014961:X-Ray Diffraction
chemical_list: D015801:Helminth Proteins; D012556:Schistosomicides; D006655:Histone Deacetylases