Schistosoma Epigenetics - Targets, Regulation, New Drugs
         SEtTReND

    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 the cloned target protein to the lead compound. 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. Initially all members of HDAC classes I, II and III (sirtuins) HAT, HMT and HDM encoded in the genome will be identified. In parallel, a reverse genetics approach using generic inhibitors of HME subclasses 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 modelized 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 drugs. 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 trials.