To develop a platform to study protein-protein interactions.
The biomedical field is under increasing pressure to accelerate the discovery and development of innovative therapeutic thus limiting the investigations to well established families of drug target. Indeed, the 100 best-selling drugs used worldwide target less than 50 different proteins, leaving a considerable opportunity in identifying innovative drug targets. Most drug discovery initiatives develop and/or expand their pre-clinical and clinical pipelines focusing on G-protein coupled receptors, nuclear receptors, ion channels and enzyme active sites. While this situation is understandable for historical and risk management reasons, protein-protein interaction inhibitors represent a huge, essentially untouched diverse group of key targets for therapeutic intervention. Despite these challenges, several lines of evidence provide hope for finding small molecules that target protein-protein interfaces. Although these interfaces are large, mutational studies show that a small subset of the residues involved contributes most of the free energy of binding. Such 'hotspots' constitute less than half of the contact surface of a protein involved in the protein-protein interaction and are usually found at the centre of the contact interface. Research into finding small molecules that disrupt protein-protein interfaces has made considerable progress in the past seven years. These examples are particularly instructive because crystal structures that are publicly available in the Protein Data Bank (PDB) allow comparison of the protein-protein complexes and the protein-small-molecule complexes. This provides the opportunity to analyse structurally how a small molecule directly competes with a natural protein partner. In collaboration with Bruno Villoutreix, we have analyzed all the published structures and derived consensus features that can be introduced in novel compounds. To synthesize these compounds, we have developped condensation reactions that have a high CsEI (Complexity of synthesis Efficiency Index), derived from Meyers work or IMCRs (Isonitrile Multi-Component Reactions). Using the repertoire of reactions that we have developed, and our catalogue of reagents, we are constantly feeding a virtual library of compounds that are screened in silico on several models by Bruno Villoutreix et al. The highest ranking compounds and there close congeners are then synthesized. To test the relevance of the discovery strategy proposed, p53-HDM2, a benchmark model for the study of protein-protein interactions has been selected as a first exercise. Other protein-protein interactions studied are bfl1-bax, scramblase-CD4,…
We have expressed HDM2 and developed an assay to test the interactions between p53 and MDM2. Several hits have been found and are currently being optimized. More than 20000 compounds have been selected through in silico screening and screened for inhibition of the bfl1-bax interaction.
Recently we started a project aiming at targeting protein-protein interactions in HCV infection.
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Funding
