Molecular Basis for the Antiparasitic Activity of a Mercaptoacetamide Derivative That Inhibits Histone Deacetylase 8 (HDAC8) from the Human Pathogen Schistosoma mansoni

• Published in: Journal of molecular biology 2014-10, Vol.426 (20), p.3442-3453
• Main Authors: Stolfa, Diana A., Marek, Martin, Lancelot, Julien, Hauser, Alexander-Thomas, Walter, Alexandra, Leproult, Emeline, Melesina, Jelena, Rumpf, Tobias, Wurtz, Jean-Marie, Cavarelli, Jean, Sippl, Wolfgang, Pierce, Raymond J., Romier, Christophe, Jung, Manfred
• Format: Article
• Language: English
• Subjects: Animals; antiparasitic activity; Antiparasitic Agents - chemistry; Antiparasitic Agents - metabolism; Antiparasitic Agents - pharmacology; Apoptosis - drug effects; Biocatalysis - drug effects; Biochemistry, Molecular Biology; Crystallography, X-Ray; docking; epigenetics; Helminth Proteins - antagonists & inhibitors; Helminth Proteins - chemistry; Helminth Proteins - metabolism; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - metabolism; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - chemistry; Histone Deacetylases - metabolism; Humans; Hydroxamic Acids - chemistry; Hydroxamic Acids - metabolism; Hydroxamic Acids - pharmacology; Inhibitory Concentration 50; Life Sciences; Models, Molecular; Molecular Structure; Protein Binding; Protein Structure, Tertiary; Schistosoma mansoni - drug effects; Schistosoma mansoni - enzymology; Schistosoma mansoni - physiology; Schistosomiasis mansoni - parasitology; Thioacetamide - chemistry; Thioacetamide - metabolism; Thioacetamide - pharmacology; thiol; X-ray crystallography
• ISSN: 0022-2836; 1089-8638; 1089-8638
• DOI: 10.1016/j.jmb.2014.03.007

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 structure 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. [Display omitted] •Species-selective inhibitors of smHDAC8 are sought as antiparasitic agents.•Focused library screening identified several reference HDAC inhibitors as inhibitors of both human HDAC8 and smHDAC8.•A mercaptoacetamide inhibitor is fourfold more selective for the parasite isotype and an ester prodrug inhibits cultured parasites with induction of apoptosis.•The structure of this inhibitor with smHDAC8 was solved and is the first X-ray structure of any mercaptoacetamide in complex with an HDAC of any origin.•Structure-based optimization of the lead inhibitor will allow for more potent and selective inhibitors of smHDAC8 as antiparasitic agents.