PCV - Programme interdiciplinaire en physique et chimie du vivant

INHIBITION SÉLÉCTIVE DES INTÉRACTIONS PROTÉINE-PROTÉINE: LES DOMAINES PDZ IMPLIQUÉS DANS LE CANCER ET LA DOULEUR NEUROPATHIQUE – PDZ-CANPAIN

Submission summary

In 2007, the FDA approved only 17 new drugs, of which 4 were indicated in the treatment of cancer and 2 for the treatment of CNS-related diseases. Beside increased levels of regulatory caution, the scarcity of new drugs also results from the lack of novel targets. To overcome this target shortage, some are turning to novel classes of drugs, including inhibitors of protein-protein interactions (PPI) and multi-target drugs. PPIs play a central role in most regulatory processes and diseases mechanisms. This programme is concerned with one of the most common PPI : the PDZ domain named after post-synaptic density/discs large/zona occludens-1. PDZ domains are small 90 amino acid domains and over 450 of these are encoded by the human genome. The domain binds predominantly to the C-terminus of protein ligands. The most prominent roles of these domains are to cluster and co-localise transporters, channels and signalling proteins in specific sub-cellular domains, determine the polarised localisation of many proteins, control channel and transporter function and regulate endocytic trafficking. Being one of the most common PPI, the PDZ-mediated machinery is fundamental to cell function. There has been much speculation in high profile publications about the potential of PDZ domains as drug targets. Reports have started to emerge of their significance in disease pathways. However, before these domains can be 'druggable' it is essential that we probe the functions of PDZ interactions to determine whether they can be effectively manipulated and whether this can be done selectively, given the large number of PDZ-containing proteins. We propose to probe PDZ-containing proteins involved in disease development (cancer and neuropathic pain) and selectively inhibit PPI by blocking the PDZ pocket and groove with non-peptide small molecules. Since PDZ domains share about 25% identity in sequence, core features about the way they bind to targets are apparent. It is therefore tempting to speculate that it would be possible to : 1) identify generic binders to the conserved binding pocket for each class of PDZ domains (S0) by exploiting the diversity in the first residue of the second helix, and 2) confer specificity by extending these generic compounds to incorporate functional groups which would be specific for binding to an individual PDZ-containing protein (S1). The generation of these bi-ligands should provide a useful insight into the structure, function, selectivity and specificity of PDZ domains and would speed up the discovery of new selective inhibitors of PDZ domains; given their large numbers encoded by the human genome, an improvement on the current situation is required.

Project coordination

Sylvie DUCKI (Université)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

Help of the ANR 350,000 euros
Beginning and duration of the scientific project: - 48 Months

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