Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/11442
Title: Targeting schistosome histone modifying enzymes for drug development
Authors: Pierce, Raymond John
Abdesselem, Florence Dubois
Lancelot, Julien
Macedo, Luiza Freire de Andrade e
Oliveira, Guilherme Correa de
Affilliation: Institut Pasteur de Lille. Lille, France/Universite Lille Nord de France. Lille, France
Institut Pasteur de Lille. Lille, France/Universite Lille Nord de France. Lille, France
Institut Pasteur de Lille. Lille, France/Universite Lille Nord de France. Lille, France
Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Centro de Excelencia em Bioinformatica, Genomica e Grupo de Biologia Computacional. Belo Horizonte, MG, Brazil/Instituto Nacional para Ciencia e Tecnologia em Doenças Tropicais
Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Centro de Excelencia em Bioinformatica, Genomica e Grupo de Biologia Computacional. Belo Horizonte, MG, Brazil/Instituto Nacional para Ciencia e Tecnologia em Doenças Tropicais
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
Issue Date: 2012
Publisher: Bentham Science Publishers
Citation: PIERCE, Raymond John et al. Targeting schistosome histone modifying enzymes for drug development. Current Pharmaceutical Design, vol.18, n. 24, p. 3567-3578, 2012.
DOI: 10.2174/138161212801327248
ISSN: 1381-6128
Copyright: restricted access
Appears in Collections:MG - IRR - Artigos de Periódicos

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