Design and Synthesis of Conformationally Constrained Helix Peptides for Disruption of Protein-Protein Interactions in Chemical Biology and Drug Disc

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Protein-protein interactions (PPIs) are essential in almost every biological process. The ability to regulate PPIs using chemical probes is therefore extremely important for studying the nature of these molecular recognition events and the development of novel therapeutics. Conformationally constrained "stapled" peptides have recently come of age as tools to disrupt PPIs that are mediated by an helix. We recently developed a novel type of constrained peptide based on a diyne "girder" that acts as a more effective conformational constraint than the current state of the art.The aim of this project is to further develop this novel, enabling technology and apply to the disruption of histone deacetylase (HDAC) corepressor protein complexes in collaboration with the Schwabe Group (Institute of Chemical and Structural Biology, University of Leicester).HDAC enzymes are important components of an epigenetic regulatory network that is essential for the control of gene regulation. Several HDAC inhibitors are in clinical use for the treatment of cancer, and may be useful for the treatment of Alzheimer's disease. However, despite many promising results there are significant drawbacks with using existing HDACi as therapeutic agents. We will develop isoform selective HDACi and thus produce a better therapeutic index.