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

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

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: PLOS Pathogens. Volume 9, issue 9 (2013), e1003645, DOI 10.1371/journal.ppat.1003645, issn: 1553-7374 ; IN COPYRIGHT http://rightsstatements.org/page/InC/1.0 rs

Classification and Topics

• Keyword: Kristallstruktur ; Enzym ; Krebs ; Schistosoma mansoni ; Parasitäre Krankheit ; Enzym ; Infektion ; Infektiologie

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2013
• Creator: Marek, Martin ; Kannan, Srinivasaraghavan ; Hauser, Alexander-Thomas ; Sippl, Wolfgang ; Jung, Manfred
• Contributor: Albert-Ludwigs-Universität Freiburg. Institut für Pharmazeutische Wissenschaften ; Albert-Ludwigs-Universität Freiburg. Fakultät für Chemie und Pharmazie ; Albert-Ludwigs-Universität Freiburg. Freiburg Institute of Advanced Studies ; Albert-Ludwigs-Universität Freiburg

Further information

• DOI: 10.1371/journal.ppat.1003645
• URN: urn:nbn:de:bsz:25-freidok-130116
• Rights: Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 20.08.22255, 8:38 AM CEST