1,3-Diyne Constrained alpha-Helix Peptides: New tools for Interrogating Protein-Protein Interactions

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In this research project, we will develop an innovative new experimental method to conformationally constrain peptides to fold into an alpha-helix secondary structure. The resulting molecules will be useful chemical tools for the regulation of protein-protein interactions.Protein-protein interactions are involved in the regulation of cellular functions and represent attractive targets to medicinal chemists. While these molecular recognition events involve interactions over large surface areas, the majority of the binding affinity and specificity has been found to originate from constellations of a few amino acid residues that are described as interaction 'hotspots'. At a molecular level, these constellations of residues are frequently found to be specific protein secondary structures such as the alpha-helix, beta-strand/sheet and turn conformations. These structural motifs present molecular functionality with the correct orientation and spacing to interact with complementing functionality on the partner protein. Although the helical motif is usually thermodynamically favoured in folded proteins, isolated peptides typically lack the ability to spontaneously adopt the helical conformation. Efforts to excise specific helical motifs from an active protein sequence have thus necessitated synthetic modifications to link distant residues to induce an alpha-helix conformation. These conformational constraints have been used to produce alpha-helical peptide mimics for probing protein-protein interaction binding surfaces and have in some instances furnished lead compounds for drug discovery. However, in many examples the functionality linking the distant amino acid residues is too flexible to induce helical structure and so does not act as a conformational constraint or improve the physicochemical properties of the peptide. In this project we will address this challenge by developing a highly rigid conformational constraint based on a 1,3-diyne side-chain to side-chain bridge and produce functional tool compounds to investigate protein-protein interactions.