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Biol Aujourdhui. 2016;210(4):311-320. doi: 10.1051/jbio/2017001. Epub 2017 Mar 22.

Combattre les maladies négligées en ciblant sélectivement leurs enzymes épigénétiques : le cas de la désacétylase 8 (HDAC8) de Schistosoma mansoni.

[Article in French]

Author information

1
Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UDS), CNRS, INSERM, 67404 Illkirch Cedex, France.
2
Institute of Pharmaceutical Sciences, University of Freiburg, 79104 Freiburg, Germany.
3
Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle/Saale, Germany.
4
Université de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d'Infection et d'Immunité de Lille, 59000 Lille, France.

Abstract

Chromatin structure in eukaryotes and its modulation by epigenetic mechanisms enable the regulation of the different nuclear processes. Perturbation of epigenetic mechanisms can thus affect the proper functioning of cells, and numerous diseases have been linked to the deregulation of the activity of epigenetic effectors in human. The reversibility of epigenetic mechanisms has allowed the development of "Epigenetic drugs" or "Epidrugs". In a chemical biology approach, we have made use of the importance of eukaryotic epigenetic mechanisms to find drug leads that specifically affect pathogens responsible for neglected diseases. Our work on histone deacetylase 8 from Schistosoma mansoni (smHDAC8) has enabled us to design drug leads that show stronger selectivity for the pathogen enzyme than for its human homologs. Specifically, we have used a structure-based approach to understand the structural specificities of the smHDAC8 enzyme compared to the human enzymes, notably human HDAC8. The structure of smHDAC8 in complex with various pan-HDAC drugs led to the design of inhibitors that make use of all the structural specificities of this enzyme and that can be stabilized in the smHDAC8 catalytic pocket through a pathogen-specific clamp. Collectively, our results provide the proof of concept that epigenetic enzymes from pathogens can be targeted to develop anti-pathogenic epidrugs in the fight against neglected diseases. Our results also provide information that can be used to develop epidrugs to fight human diseases, including cancer.

PMID:
28327287
DOI:
10.1051/jbio/2017001
[Indexed for MEDLINE]

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