Versatile Oligoamide α-helix Mimetic Scaffolds

Protein-protein interactions (PPIs) play a pivotal role in mediating a number of biological processes involved in the development of infected or diseased states. Since α-helices constitute the most abundant motif at characterised protein interfaces, α-helix mediated PPIs represent an attractive target for therapeutic intervention and their inhibition with α-helix mimetics has emerged as a powerful strategy. Encouraging results have been obtained through the design of foldamers and proteomimetics and the current state-of-the-art is described in Chapter 1.

The Wilson group is interested in the development of aromatic oligoamide α-helix mimetics. The work presented in this thesis was therefore aimed at developing a better understanding of the conformational properties of this family of proteomimetics through screening against two key oncogenic targets, p53/hDM2 and Mcl-1/NOXA B, in order to identify key features required to reproduce the functional role of α-helices and achieve effective inhibition.

A 2-O-alkylated oligobenzamide scaffold was designed to determine the effect of non-covalent interactions on the conformational preference and molecular recognition properties of these oligomers. The conformational studies performed on regioisomeric 2-O and 3-O-alkylated dimers are described in Chapter 2, whilst the biophysical assessment of trimers of both series for p53/hDM2 inhibition is reported in Chapter 3.

These studies pointed to a complex interplay of interactions influencing the conformational and protein recognition properties of these mimetics and led to design of a new hybrid -helix mimetic scaffold. Chapter 4 describes the conformational studies and structure-activity relationship data obtained from biological assays of a 35-membered library built using a robust solid-phase strategy. This scaffold allowed the identification of the first examples of enantioselective recognition of type III mimetics by different proteins and enantiodependent differentiation of mimetics by a protein partner, and represents a potential starting point to elaborate rule based approaches for the design of proteomimetics aimed at effective PPI inhibition