Design and Synthesis of Functional Aromatic Oligoamide Foldamers

Although many cellular processes depend upon enzymatic reactions, protein-protein interactions populate a significant number of regulatory pathways - thus an explosion of interest in their study mirrors a pivotal role in diseased states. In order to effectively manipulate biological systems, there is a pressing need for small molecules that inhibit these interactions through strong and selective recognition of the interacting surfaces. What is not clear is how to achieve this using a small molecule. In the 'proteomimetic' approach a scaffold is used to project binding functionality in an identical spatial orientation to mimic that presented by a given secondary structure involved in the interaction. A related area of research is concerned with 'foldamers' (self-organising synthetic oligomers). Foldamers attempt to replicate the ability of biopolymers to self-organise and present functional motifs e.g. an active site, through precise 3-D orientation of primary structure. Proteomimetics and foldamers therefore present functionality in a well-defined spatial orientation and amongst a plethora of possible applications, the later if suitably designed will function as inhibitors of protein-protein interactions. However, synthesis of foldamers is in general limited to identical monomer units and solution phase, so the functionality they possess and variety of different sequences is limited. In the current project we will develop two series of foldamers based upon an aromatic oligoamide scaffold. These are attractive because in addition to predictable folding, they are amenable to solid phase synthesis. By developing the necessary synthetic methodology we will be capable of rapid access to a variety of oligomer sequences. These will allow us to: (i) study the self-organisation of our oligomers, resulting in a greater appreciation of self-organisation phenomena and (ii) test the ability of our oligomer sequences to mimic alpha helices and act as inhibitors of protein-protein interactions, thus developing a tool that may be useful in a pharmaceutical context.