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

PLoS Pathog. 2013;9(9):e1003645. doi: 10.1371/journal.ppat.1003645. Epub 2013 Sep 26.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Epigenesis, Genetic*
  • Helminth Proteins / chemistry*
  • Helminth Proteins / genetics
  • Helminth Proteins / metabolism
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylases / chemistry*
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Humans
  • Protein Folding*
  • Protein Structure, Secondary
  • Schistosoma mansoni / enzymology*
  • Schistosoma mansoni / genetics

Substances

  • Helminth Proteins
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases

Grant support

This project and the authors of this manuscript were financed by the European Community grant SEtTReND (FP7-Health contract no. 241865). This work was also supported by institutional funds from the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the Université de Lille 2, the Université de Strasbourg (UDS), the French Infrastructure for Integrated Structural Biology (FRISBI), and from contracts CNPq (306879/2009-3, 480576/2010-6 and 573839/2008-5) and FAPEMIG (PPM-00439-10). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.