Titre :

Structural Basis for the Inhibition of Histone Deacetylase 8 (HDAC8), a Key Epigenetic Player in the Blood Fluke Schistosoma mansoni

Auteur(s) :

Marek, Martin [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
Kannan, Srinivasaraghavan [Auteur]
Martin-Luther-Universität Halle Wittenberg [MLU]
Hauser, Alexander-Thomas [Auteur]
Albert-Ludwigs-Universität Freiburg = University of Freiburg
Moraes Mourão, Marina [Auteur]
Fundação Oswaldo Cruz / Oswaldo Cruz Foundation [FIOCRUZ]
Caby, Stéphanie [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Cura, Vincent [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
Stolfa, Diana [Auteur]
Albert-Ludwigs-Universität Freiburg = University of Freiburg
Schmidtkunz, Karin [Auteur]
Albert-Ludwigs-Universität Freiburg = University of Freiburg
Lancelot, Julien [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Andrade, Luiza [Auteur]
Fundação Oswaldo Cruz / Oswaldo Cruz Foundation [FIOCRUZ]
Renaud, Jean-Paul [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
Oliveira, Guilherme [Auteur]
Fundação Oswaldo Cruz / Oswaldo Cruz Foundation [FIOCRUZ]
Sippl, Wolfgang [Auteur]
Albert-Ludwigs-Universität Freiburg = University of Freiburg
Jung, Manfred [Auteur]
Albert-Ludwigs-Universität Freiburg = University of Freiburg
Cavarelli, Jean [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
Pierce, Raymond [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Romier, Christophe [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]

Titre de la revue :

PLoS pathogens

Éditeur :

Public Library of Science

Date de publication :

2013-09-26

ISSN :

1553-7366

Discipline(s) HAL :

Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire/Biologie structurale [q-bio.BM]
Sciences du Vivant [q-bio]/Microbiologie et Parasitologie/Parasitologie
Chimie/Chimie thérapeutique

Résumé en anglais : [en]

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 ...
Lire la suite >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 a/b 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.Lire moins >

Langue :

Anglais

Comité de lecture :

Oui

Audience :

Internationale

Vulgarisation :

Non

Projet ANR :

Infrastructure Française pour la Biologie Structurale Intégrée

Collections :

• Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017

Source :

Harvested from HAL