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

Abstract

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.

HDAC8: a multifaceted target for therapeutic interventions

“…In a second study, an inhibitor bearing a mercaptoacetamide (1a) warhead ( Figure 4B) showed specificity for smHDAC8 over hHDAC8 (Table 1) [87]. The structure in complex with smHDAC8 revealed a specific binding mode of its warhead to the catalytic zinc and a flipping-in of the smF151 side chain, whereas smH292 was not involved in inhibitor binding ( Figure 5F) [87].…”

“…The structure in complex with smHDAC8 revealed a specific binding mode of its warhead to the catalytic zinc and a flipping-in of the smF151 side chain, whereas smH292 was not involved in inhibitor binding ( Figure 5F) [87]. Both linkerless hydroxamates and mercaptoacetamide induced apoptosis in cultured worms.…”

“…Data on different subcellular locations (nuclear versus cytoplasmic) of HDAC8 [43,89] implicate a context-dependent action of its inhibitors and may help to define specific disease subsets, such as in cancer, for treatment. [24,87]. The secondary structure elements of smHDAC8 are shown as light-brown ribbons.…”

“…or trypanosomiasis [90][91][92]. Structure-based studies on smHDAC8 inhibitors may be considered a model approach for speciesselective inhibitors in such diseases [24,87] and may also extend to, for example, fungi [93]. For antiviral therapy, preclinical tests of specific HDAC8 inhibitors will provide valuable insight into its druggability in this context.…”

Compounds from African Medicinal Plants with Activities against Protozoal Diseases: Schistosomiasis, Trypanosomiasis and Leishmaniasis

“…20 Moreover, observed resistance and reduced efficiency of praziquantel in laboratory strains have prompted the search for alternative therapeutic strategies. [20][21][22][23][24][25][26][27] Trypanosomiasis, which represents several diseases caused by parasites of the genus Trypanosoma, is also of interest. 5,27,29 This disease, which is much arguably the most important disease of man and domesticated animals, accounts for over 8 million reported annual cases globally, especially in the tropical regions of Latin America and Africa.…”