Protein-Protein interactions

Team

  • Florence Leroux PhD
  • Cyril Couturier PhD – Assistant Pr
  • Adrien Herledan - Engineer

Mission

To develop a platform to study protein-protein interactions.

Approach

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,…

Latest results

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.

Publications

  • Corbel, C., Zhang, B., Le Parc, A., Baratte, B., Colas, P., Couturier, C., Kosik, K. S., Landrieu, I., Le Tilly, V., & Bach, S. Tamoxifen Inhibits CDK5 Kinase Activity by Interacting with p35/p25 and Modulates the Pattern of Tau Phosphorylation. Chemistry & Biology,2015, 22(4): 482.doi:10.1016/j.chembiol.2015.03.009
  • Mathieu, A. L., Sperandio, O., Pottiez, V., Balzarin, S., Herledan, A., Elkaim, J. O., Fogeron, M. L., Piveteau, C., Dassonneville, S., Deprez, B., Villoutreix, B. O., Bonnefoy, N., & Leroux, F. Identification of Small Inhibitory Molecules Targeting the Bfl-1 Anti-Apoptotic Protein That Alleviates Resistance to ABT-737. J Biomol Screen,2014, 19(7): 1035-1046. 10.1177/1087057114534070
  • Couturier, C., & Deprez, B. Setting up a Bioluminescence Resonance Energy Transfer high throughput screening assay to search for protein/protein interaction inhibitors in mammalian cells. Frontiers in Endocrinology,2013, 3: 100.10.3389/fendo.2012.00100
  • Reynes, C., Host, H., Camproux, A.-C., Laconde, G., Leroux, F., Mazars, A., Deprez, B., Fahraeus, R., Villoutreix, B. O., & Sperandio, O. Designing Focused Chemical Libraries Enriched in Protein-Protein Interaction Inhibitors using Machine-Learning Methods. Plos Computational Biology,2010, 6(3): e1000695.
  • Beghyn, T., Deprez-Poulain, R., Willand, N., Foleas, B., & Deprez, B. Natural compounds: leads or ideas? Bioinspired molecules for drug discovery. Chemical Biology and Drug Design,2008, 72: 3-15.
    Villoutreix, B. O., Bastard, K., Sperandio, O., Fahraeus, R., Poyet, J. L., Calvo, F., Deprez, B., & Miteva, M. A. In silico-in vitro screening of protein-protein interactions: towards the next generation of therapeutics. Current Pharmaceutical Biotechnology,2008, 9(2): 103-122.
  • Deprez-Poulain, R., & Deprez, B. Trends in Hit-to-Lead: An Update. Frontiers in Medicinal Chemistry,2006, 3(1): 653-673.
  • Caroline Smet, Jean-Frédéric Duckert, Jean-Michel Wieruszeski, Isabelle Landrieu, Luc Buée, Guy Lippens, and Benoît Déprez. Control of protein-protein interactions: structure-based discovery of low molecular weight inhibitors of the interactions between Pin1 WW domain and phosphopeptides. J.Med.Chem , 2005, 48, (15), 4815-4823
  • Déprez-Poulain R, Willand N, Boutillon C, Nowogrocki G, Azaroual N, Déprez B. A simple reaction to produce small structurally complex and diverse molecules. Tetrahedron Lett. 2004; 45 (27): 5287-5290.
  • Déprez-Poulain R, Déprez B. Facts, Figures and Trends in Lead Generation. Current Topics in Medicinal Chemistry 2004; 4 (6): 569-580.

Poster communications

  • Malaquin, S., Host, H., Laconde, G., Deprez-Poulain, R., Leroux, F., & Deprez, B. Conception of protein-protein interactions inhibitors: screening and libraries synthesis 10th Journée André Verber, Lille, France, 15th Sep,2010.
  • Host, H., Malaquin, S., Laconde, G., Deprez-Poulain, R., Leroux, F., & Deprez, B. Conception of protein-protein interactions inhibitors: screening and libraries synthesis XVIime Journée Jeunes Chercheurs SCT, Paris, 5th February,2009.
  • Leroux, F., Zarka, M., Delaroche, S., Bouchet, J., Basmaciogullari, S., Déprez, B., & Benichou, S. Screening for Inhibitors of CD4-PLSCR1 Interaction, a New Target for Therapy of HIV-1 Infection 15th SBS Annual Conference, Lille, France, 26-30 Apr.,2009.
  • Host, H., Malaquin, S., Dausque, G., Laconde, G., Déprez, R., Leroux, F., & Déprez, B. Conception of protein-protein interactions inhibitors: screening and libraries synthesis 15th SBS Annual Conference, Lille, France, 26-30 Apr.,2009.

Funding

  • ARC-APP 2010 Bfl1 : Design rationnel d'inhibiteurs de Bfl_1 ; 01/01/11 - 31/12/13
  • French Research Agency ANR N° Piribio-10-PPiFocusdB : Inhibiteurs d'interactions protéine-protéine ; 01/01/10 - 31/12/12
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