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Abstract
The ubiquity and variety of protein-protein interactions (PPI) mediating the human protein interactome make them an attractive yet daunting target for investigation and therapeutic modulation. The dysregulation of these interactions is commonly associated with pathology, covering a wide range of diseases, and each of these represent a potential drug target. It is estimated that there are as many as 600,000 PPI within the human interactome, however, only 0.01% of these PPIs have been targeted by an inhibitor.As major strides are made in understanding the biochemical and biological properties of PPIs and new structural insights are provided by advances in technology, the development of molecules capable of mimicking the binding sites of proteins has seen increasing success. Natural and synthetic peptides corresponding to short fragments located at the protein-protein interface would appear to provide logical candidates for interference with PPIs. The proteinaceous α-helix is the most common secondary structure found at protein interfaces, and this provides a useful template for design of peptides which disrupt these interactions. the all-hydrocarbon stapled α-helical peptide provides a versatile platform for development of constrained peptides targeting helix-mediated interactions. The aim of this research is the application of all-hydrocarbon stapled peptides as tools for modulation of PPI within a broad range of complexes. This approach has been applied to a wide variety of proteins from scaffolding proteins and kinases to regulators of the actin cytoskeleton and cancer metastasis. This work charts the progress made through advancements in understanding of synthetic chemistry, computational peptide design, and biological characterization in the creation of all-hydrocarbon stapled peptides as tools for understanding PPI and as potential therapeutics.