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Functional Pharmacogenomics of G Protein-Coupled Receptors


The objective of the programme is to study the novel G protein-coupled receptors (GPCRs) derived from the recent knowledge of the human genome, and useselected members of them as drug targets. The partnership involves leading academic laboratories and biotechnology companies dedicated to GPCRs, which cover all aspects of target validation and early drug development. A large collection of orphan GPCRs will be studied in parallel. The distribution of these receptors will be studied in normal and diseased tissues, using a range of techniques. Cell lines expressing orphan receptors will be used for functional screening of a large collection of peptide and protein fractions from natural sources, in order to identify the natural agonists of these receptors. The active compounds will be purified, and their structure determined by mass spectrometry. Random peptide libraries will also be screened with the aim of identifying surrogate ligands.

The pharmacology and function of the newly characterised receptors will be determined in vitro, in vivo and in transgenic models. Finally, chemical libraries will be screened on receptors selected as drug targets, and leads will be optimised with the help of receptor modelling and structural studies. The molecules developed in this frame will be tested in animal models, with the aim of partnering subsequent steps of drug development with pharmaceutical industries. We expect to identify natural or surrogate ligands for about 6 orphan receptors over the three years of the programme.A number of recently characterized receptors, for which patent applications have been filed, will allow initiation of the target validation and lead development steps of the programme immediately. A patent portfolio will constitute the basis of further developments in the exploitation phase.

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