期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 426, 期 20, 页码 3442-3453出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2014.03.007
关键词
antiparasitic activity; docking; epigenetics; thiol; X-ray crystallography
资金
- European Union [241865, 602080]
- Deutsche Forschungsgemeinschaft [Ju 295/10-2, CRU201]
- Centre National de la Recherche Scientifique
- Institut National de la Sante et de la Recherche Modicale
- Universite de Strasbourg
- Universite de Lille 2
- French Infrastructure for Integrated Structural Biology [ANR-10-INSB-05-01]
- Instruct (European Strategy Forum on Research Infrastructures)
Schistosomiasis, caused by the parasitic flatworm Schistosoma mansoni and related species, is a tropical disease that affects over 200 million people worldwide. A new approach for targeting eukaryotic parasites is to tackle their dynamic epigenetic machinery that is necessary for the extensive phenotypic changes during the life cycle of the parasite. Recently, we identified S. mansoni histone deacetylase 8 (smHDAC8) as a potential target for antiparasitic therapy. Here, we present results on the investigations of a focused set of HDAC (histone deacetylase) inhibitors on smHDAC8. Besides several active hydroxamates, we identified a thiol-based inhibitor that inhibited smHDAC8 activity in the micromolar range with unexpected selectivity over the human isotype, which has not been observed so far. The crystal structura of smHDAC8 complexed with the thiol derivative revealed that the inhibitor is accommodated in the catalytic pocket, where it interacts with both the catalytic zinc ion and the essential catalytic tyrosine (Y341) residue via its mercaptoacetamide warhead. To our knowledge, this is the first complex crystal structure of any HDAC inhibited by a mercaptoacetamide inhibitor, and therefore, this finding offers a rationale for further improvement. Finally, an ester prodrug of the thiol HDAC inhibitor exhibited antiparasitic activity on cultured schistosomes in a dose-dependent manner. (C) 2014 The Authors. Published by Elsevier Ltd.
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