Chromatin regulation in schistosomes and histone modifying enzymes as drug targets

Pierce, Raymond J.; Dubois-Abdesselem, Florence; Caby, Stéphanie; Trolet, Jacques; Lancelot, Julien; Oger, Frédérik; Bertheaume, Nicolas; Roger, Emmanuel

doi:10.1590/s0074-02762011000700003

Cited by 32 publications

(19 citation statements)

References 59 publications

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“…We will therefore focus on histones and their post-translational modifications (PTM). The fundamental chromatin unit, a nucleosome, consists of two stabilized histone 3-histone 4 (H3-H4) dimers flanked by two histone histone 2A-histone 2B (H2A-H2B) dimers, as well as 147 bp of DNA wound around the complete octamer 27, 28. Each of the core histones contains an N-terminal 20–30 amino acid projection called the histone tail, with amino acids in these tails often covalently modified by PTMs.…”

Section: Element 2: the Epigenome (I)mentioning

confidence: 99%

(Epi)genetic Inheritance in Schistosoma mansoni: A Systems Approach

Cosseau

Wolkenhauer

Padalino

et al. 2017

Trends in Parasitology

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The G×E concept, in which genotype × environment interactions bring about the phenotype, is widely used to describe biological phenomena. We propose to extend the initial notion of the concept, replacing G by ‘inheritance system’. This system, comprised of both genome and epigenome components, collectively interacts with the environment to shape the development of a phenotype. In the case of the human blood fluke Schistosoma mansoni, responsible for intestinal bilharzia, the phenotypic trait that is most relevant to global health is infection success. Taking a systems biology view we show how genetic and epigenetic interactions result in ephemeral, but also heritable, phenotypic variations that are important for infection success.

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Section: Element 2: the Epigenome (I)mentioning

confidence: 99%

(Epi)genetic Inheritance in Schistosoma mansoni: A Systems Approach

Cosseau

Wolkenhauer

Padalino

et al. 2017

Trends in Parasitology

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“…The treatment of S. mansoni with small‐molecule histone deacetylase (HDAC) inhibitors was shown to cause dose‐dependent mortality of schistosomula as well as adult worms, making HDACs potential targets for the treatment of schistosomiasis . In eukaryotes, HDACs, which belong to the epigenetic machinery of the cells, catalyze the deacetylation of ϵ‐amino groups of lysine residues in histone tails, leading in consequence to a more compact chromatin structure, which usually results in an inhibition of transcription .…”

Section: Introductionmentioning

confidence: 99%

Structure‐Based Design, Synthesis, and Biological Evaluation of Triazole‐Based smHDAC8 Inhibitors

et al. 2020

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Schistosomiasis is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma, which affects over 200 million people worldwide and leads to at least 300,000 deaths every year. In this study, initial screening revealed the triazole‐based hydroxamate 2 b (N‐hydroxy‐1‐phenyl‐1H‐1,2,3‐triazole‐4‐carboxamide) exhibiting potent inhibitory activity toward the novel antiparasitic target Schistosoma mansoni histone deacetylase 8 (smHDAC8) and promising selectivity over the major human HDACs. Subsequent crystallographic studies of the 2 b/smHDAC8 complex revealed key interactions between the inhibitor and the enzyme's active site, thus explaining the unique selectivity profile of the inhibitor. Further chemical modifications of 2 b led to the discovery of 4‐fluorophenoxy derivative 21 (1‐[5‐chloro‐2‐(4‐fluorophenoxy)phenyl]‐N‐hydroxy‐1H‐1,2,3‐triazole‐4‐carboxamide), a nanomolar smHDAC8 inhibitor (IC50=0.5 μM), exceeding the smHDAC8 inhibitory activity of 2 b and SAHA (vorinostat), while exhibiting an improved selectivity profile over the investigated human HDACs. Collectively, this study reveals specific interactions between smHDAC8 and the synthesized triazole‐based inhibitors and demonstrates that these small molecules represent promising lead structures, which could be further developed in the search for novel drugs for the treatment of schistosomiasis.

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“…Subsequent studies (see [88]) also showed that pan-inhibitors of other HME subclasses, including sirtuins, histone acetyltransferases, histone methyltransferases and histone demethylases could induce apoptosis in schistosomes cultured in vitro. For example, the sirtuin inhibitor sirtinol was found to be a potent inducer of apoptosis in schistosomula.…”

Section: Schistosome Hmes As Drug Targetsmentioning

confidence: 97%

Targeting Schistosome Histone Modifying Enzymes for Drug Development

Pierce

Dubois-Abdesselem²,

Lancelot³

et al. 2012

cpd

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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. SCHISTOSOMIASIS: IMPACT OF THE DISEASE AND THE NEED FOR NEW DRUGSThe impact of schistosomiasis on communities in endemic areas extends well beyond the classical signs of morbidity: Symmer's fibrosis leading to hepato-splenomegaly, ascites, oesophageal varices, and culminating in death. These overt and catastrophic symptoms affect only a relatively small percentage of infected individuals, even if absolute numbers of annual deaths (about 280 000) are high. However, more cryptic effects such as anaemia, undernutrition, diarrhoea and chronic pelvic or abdominal pain were consistently underevaluated until a meta-analysis of a large number of previous schistosomiasis morbidity studies by King et al.[1] allowed an objective assessment. This showed that the WHO's previously estimated disability weight for schistosomiasis of 0.5%, based essentially on mortality, should be markedly revised upwards to between 2 and 15% and that the years of life lost to schistosomiasis represented a relatively small proportion of the total of years lost to disability. This reassessment of the true disease burden represented by schistosomiasis has led to the realization of the importance of reinforcing control measures.In the continuing absence of an effective infection-preventing vaccine, the only viable strategy is the mass-treatment of populations in endemic areas using the currently available drug, praziquantel. Thus the Schistosomiasis Control Initiative in Africa [2] had dispensed more than 40 million praziquantel treatments in eight sub-Saharan countries by 2008. This ongoing programme will undoubtedly have a major impact, both on...

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Chromatin regulation in schistosomes and histone modifying enzymes as drug targets

Cited by 32 publications

References 59 publications

(Epi)genetic Inheritance in Schistosoma mansoni: A Systems Approach

(Epi)genetic Inheritance in Schistosoma mansoni: A Systems Approach

Structure‐Based Design, Synthesis, and Biological Evaluation of Triazole‐Based smHDAC8 Inhibitors

Targeting Schistosome Histone Modifying Enzymes for Drug Development

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