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

PLoS Pathogens

Julien Lancelot¹  Stéphanie Caby¹  Martin Marek²  Vincent Cura²  Christophe Romier²  Jean-Paul Renaud²  Manfred Jung³  Raymond J. Pierce³  Marina Moraes Mourão⁴  Guilherme Oliveira⁴  Luiza Andrade⁴  Karin Schmidtkunz⁵  Jean Cavarelli⁵  Alexander-Thomas Hauser⁵  Diana A. Stolfa⁵  Wolfgang Sippl⁶  Srinivasaraghavan Kannan⁶ 

[1] Center for Infection and Immunity of Lille (CIIL), INSERM U1019 – CNRS UMR 8204, Université Lille Nord de France, Institut Pasteur de Lille, Lille, France;Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UDS), CNRS, INSERM, Illkirch, France;Freiburg Institute of Advanced Studies (FRIAS), Albert-Ludwigs-Universität Freiburg, Freiburg, Germany;Genomics and Computational Biology Group, Center for Excellence in Bioinformatics, National Institute of Science and Technology in Tropical Diseases, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil;Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany;Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany

关键词: Schistosoma;    Parasitic diseases;    Schistosoma mansoni;    Enzyme structure;    Phenylalanine;    Zinc;    Enzyme inhibitors;    Epigenetics;   

DOI  :  10.1371/journal.ppat.1003645

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY