Scientists have long tried to imitate the efficiency, specificity and fidelity of the molecular machinery that operates in Nature. The folding of biomolecules, composed of linear arrays of relatively simple building blocks, into well-defined architectures is of fundamental importance in achieving the desired specificity in function. Organic chemists have tried to mimic this process by constructing synthetic structures, called foldamers, which adopt well-defined conformations as a result of non-covalent interactions. This thesis describes foldamers that, in the 'folded' form, mimic the position and projection of residues on one face of an a-helix and their applications in disrupting protein-protein interactions.

A family of foldamers composed of oligoarylamide backbones was designed to mimic the natural curvature found in a majority of α-helices in protein crystal structures. The curvature can be tuned by modifying the hydrogen-bonding characteristics of these simple compounds through the choice of appropriate building blocks, i.e. by switching from phenyl ring to pyridine. This knowledge adds to the repertoire of tools available for the effective mimicry of protein secondary structures by choosing a scaffold that most closely mimics the α-helix of interest.

Longer oligomers based on these scaffolds were shown to effectively inhibit the lipid-catalyzed aggregation of Islet Amyloid Polypeptide (IAPP), which has been implicated in amyloidogenesis in type II diabetes. The effect was directly dependent on the number, nature and arrangement of the negative charges in these molecules. Mechanistic investigations suggest that, unlike other known amyloid inhibitors, these molecules act by binding to the α-helical intermediates during the nucleation stages in IAPP amyloidogenesis. Since IAPP amyloid toxicity is primarily associated with the cell membrane in vivo, these compounds have great potential in the development of lead molecules for novel drugs to treat type II diabetes.

Another series of α-helix mimetic foldamers was designed to inhibit the interaction of interleukin-2 (IL-2) with the α-subunit of its receptor; a protein-protein interaction that plays a crucial role in immune disorders. The synthesized molecules were tested in an in vitro ELISA assay and one of them showed promising inhibitory activity with an inhibition constant (K_i) of ∼4 μM.