Targeting Schistosome Histone Modifying Enzymes for Drug Development

Author(s): Raymond J. Pierce, Florence Dubois-Abdesselem, Julien Lancelot, Luiza Andrade, Guilherme Oliveira.

Journal Name: Current Pharmaceutical Design

Volume 18 , Issue 24 , 2012

Abstract:

The histone modifying enzymes (HME) represent particularly promising targets for the development of alternatives to praziquantel, the only currently available drug to combat schistosomiasis. The inhibition of these enzymes frequently arrests the cell cycle or induces apoptosis in cancer cells, but not in normal cells and numerous HME inhibitors are under investigation as potential anticancer agents. The recent resolution of the genome sequences of Schistosoma mansoni and Schistosoma japonicum has allowed us to identify all the schistosome genes encoding histone acetyltransferases, deacetylases, methyltransferases and demethylases. We have chosen a strategy using phylogenetic screening with inhibitors of HME classes, screening of individual HME targets by both high-throughput and reasoned (in silico docking using resolved crystal structures) approaches in a project funded by the European Community, named SEtTReND (Schistosome Epigenetics: Targets, Regulation, New Drugs). The initial focus is on the class I histone deacetylase (HDAC) 8 since the comparison of the catalytic site of the schistosome and human enzymes shows crucial differences, rendering possible the development of inhibitors specific for SmHDAC8. However, phenotypic screening shows that inhibitors of all HME classes tested were able to induce apoptosis and death in parasites in vitro, indicating that other enzymes may prove to be viable targets.

Keywords: Schistosoma mansoni, histone modifying enzyme, histone deacetylase, inhibitor, drug target, praziquantel, apoptosis, schistosome genes, SEtTReND, SmHDAC8

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Article Details

VOLUME: 18
ISSUE: 24
Year: 2012
Page: [3567 - 3578]
Pages: 12
DOI: 10.2174/138161212801327248
Price: $58

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