Regiospecific, Controlled Synthesis of Structurally Defined Peptide Scaffolds

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Noncovalent interactions between proteins are used in all living systems as an essential means of transferring and processing information and as such protein-protein interactions are fundamental to regulating life on a cellular level. Disruption of natural binding partners or alterations in the expression levels of a particular protein can perturb the balance of this signaling process and lead to the onset of a range of diseases. Altered protein-protein interactions are present in cancers, HIV, and Alzheimer's and inhibiting the abnormal protein-protein interactions associated with these diseases offers an exciting new avenue to develop highly selective drug molecules. However, despite considerable research efforts, identifying inhibitors of disease-associated protein-protein interactions has proven to be very challenging. The large binding surfaces present in most protein-protein interactions has meant that effective inhibitors based on small molecules have been hard to identify, but larger compounds, such as cyclic peptides that can be used to mimic protein binding surfaces, have emerged as a promising therapeutics leads. At the cutting edge of this field is the application of multicyclic peptide scaffolds, as the 3-dimensional structure of these compounds can be designed to allow multiple binding regions on a protein interface to be targeted simultaneously. But progress into designing new inhibitors of protein-protein interactions using this approach is severely hampered by a lack of viable synthetic routes to multicyclic peptide scaffolds. Utilising novel fluoropyridine amino acids as the key building blocks we will develop synthetic strategies to access multicyclic peptide scaffolds, each with a defined 3-dimensional structure. The methodology developed will also permit the formation of the peptide scaffolds in a highly controlled and regionspecific manner which is something that is not currently possible using existing technologies. Having access to multicyclic peptide scaffolds will help to accelerate the discovery of inhibitors of protein-protein interactions and thus the development of new drug molecules to target diseases such as cancer.