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

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.

This research project has the potential to have significant and wide-ranging impact. Our aim is to develop the chemistry required to produce new peptide tools that will be used to regulate protein-protein interactions.
The new chemical biology tools we propose could impact a diverse range of beneficiaries including academics, the pharmaceutical industry and the general public. We plan to engage with beneficiaries in academia and the pharmaceutical industry through dissemination of our research results in high impact journals, at conferences (both home and abroad) and through professional networks (e.g. Protein-Protein Interaction Network). The general public will also be engaged with our research using news articles appearing on our website and through social networking sites.
Conformationally constrained peptides are a potential new class of therapeutic agent that possess the high affinity and specificity of biologics (i.e. protein therapeutics) and also the pharmacokinetic properties of small molecules. Our second objective in this project is to produce conformationally constrained peptide mimics of the SMRT corepressor and assess its ability to regulate the HDAC3/corepressor protein-protein interaction. At this stage we will seek to protect the intellectual property associated with potential lead compounds and use this as leverage to obtain funding to establish a spinout company. This company will have a positive impact on the UK economy by providing employment and training for skilled workers. If successful, the company would also have a positive impact on peoples health and well being by providing improved therapeutics.
The postdoctoral researcher will present the proposed research at the Houses of Parliament as part of the SET for Britain competition. We will use this as a platform to engage with politicians in order to influence UK scientific policy.