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Helminth diseases Projects

Schistosoma Epigenetics - Targets, Regulation, New Drugs

EC contribution
: € 3,300,000
Duration
: 36 months
Starting date
: 01/01/2010
Funding scheme
: Focused research project
Contract/Grant agreement number
: 241865
Project web-site
: http://settrend.cebio.org/

Keywords: Schistosoma, histone modifying enzyme, epigenetics, molecular modelling, high-throughput screen, inhibitor, RNAi, gene expression signature, drug

Summary:

We propose to develop novel drug leads for the therapy of the major human parasitic disease, schistosomiasis, using a holistic approach that will enable us to progress from cloned target proteins to lead compounds and from epigenetic inhibitors to the validation of crucial targets. For this, we have chosen to target the histone modifying enzymes (HME) : histone deacetylases (HDAC), histone acetyltransferases (HAT), histone methyltransferases (HMT) and histone demethylases (HDM) of Schistosoma mansoni. In the course of the project, the members of the HDAC, HAT, HMT and HDM families encoded in the genome will be identified. In parallel, a reverse chemical genetics approach using generic inhibitors of HME subclasses available within the consortium in cultures of schistosome larvae will identify those classes that are bona fide drug targets. These enzymes will be validated as therapeutic targets individually or collectively using RNAi to invalidate the corresponding genes. Potential inhibitors (HDACi, HATi, HMTi, HDMi) will be screened by in silico docking to the modelled catalytic domains of the enzymes and collections of analogues will be tested for their ability to inhibit the activity of the corresponding recombinant proteins in high-throughput assays. We will also establish gene expression profiles corresponding to HME invalidation (by RNAi) and inhibition (using drug candidates in cultured larval stages (schistosomula)) that will enable the determination of the specificity of action of the compounds. Finally, in vivo testing of the best candidates will be done in infected mice. In this way, during the study period we aim to develop a series of candidate molecules that can progress to clinical
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