Who we are?

SEtTReND is a European research network (collaborative project) coordinated by Dr. Raymond Pierce from the National Institute for Health and Medical Research (INSERM), the National Center for Scientific Research (CNRS) and the Lille Pasteur Institute. The consortium brings together leading groups in the field of schistosome molecular biology with leaders in the field of drug development. It consists of 9 partners from 3 Member States of the European Union (France, Germany and Sweden) and 3 different states within Brazil, a country endemic for schistosomiasis. The project was constructed in order to achieve optimal complementarity and is supported by the European Commission under the Health priority of the 7th Framework Programme.

Context

Schistosomes are flatworm parasites that infect about 200 million individuals in over 75 countries in tropical or sub-tropical regions and cause more than 280,000 deaths annually. The burden of disease, measured in DALYS (disability adjusted life years), has recently been shown to be much more severe than previously thought. Schistosomiasis is consequently the second most important parasitic disease of man after malaria, but is also a neglected disease and only one effective drug is currently available. Moreover, reduced efficacy of this drug and resistant parasite strains are increasingly reported.

Our strategy

We propose to develop novel drug leads for the therapy of the major human parasitic disease, schistosomiasis. We will use multiple approaches that will enable us to identify targets and progress to candidate drugs. For this, we have chosen to target the enzymes that control global gene expression by modifying the histones. These proteins in turn control the packaging of DNA into chromatin and hence, its accessibility to the transcriptional machinery. The different aspects of our strategy are as follows:

• Identify the histone modifying enzymes (HME) encoded in the Schistosoma mansoni genome using bioinformatics.
• Clone and produce recombinant proteins.
• Validate these enzymes as targets.
• Test generic inhibitors of HMEs for their effects on parasites in culture.
• Use computational approaches to model the proteins and identify potential specific inhibitors.
• Use high-throughput screens and subsequent synthetic optimization to identify specific inhibitors of selected HMEs.
• Test the efficacy of selected specific inhibitors on the parasites.

In this way, during the study period we aim to develop a series of candidate molecules that can progress to clinical trials.

Our aims

The SEtTReND project aims to characterize novel therapeutic targets, concentrating in particular on enzymes involved in the modification of chromatin and therefore in controlling gene transcription, and to develop inhibitors of these enzymes that will be lead compounds for drug development.

The SEtTReND consortium intends to characterize and clone most of the enzymes involved in histone acetylation / deacetylation and methylation / demethylation. Promising candidates will be expressed as recombinant proteins and the structures of their catalytic domains will be determined by crystallography or in silico modelling. Phenotypic profiling using RNAi and generic inhibitors of histone modifying enzymes will validate potential targets and generate gene expression profiles that will define specific inhibition. Inhibitors will be validated both in silico and in vitro and optimised drug candidates will be tested in vivo.

Expected outcomes

Overall the SEtTReND partners expect to generate several candidate schistosomicidal drugs that will go forward for further testing.The principal applications will be the improvement of the chemotherapy of schistosomiasis. However, in addition to improving knowledge of histone modifying enzymes and their evolution, the development of inhibitors may well also provide leads to improving their application to the therapy of other diseases, including both parasitic infections and cancer.