Towards Bionic Proteins

De novo design of foldamers is a current challenge in chemical biology. Overcoming it is essential in order to expand the protein toolbox and access “bionic proteins”, i.e. proteins comprising non-natural segments, with enhanced biological functions. Since the alpha-helix represents the most abundant motif in protein structure, alpha-helix mimicry is a key approach to building foldamers and a stepping-stone towards generating bionic proteins. The current state-of-the-art on bottom-up foldamer synthesis for the mimicry of alpha-helices is described in Chapter 1. The Wilson Group focuses on aromatic oligoamide proteomimetics for the modulation of protein-protein interactions (PPIs) involved in known diseases. The work presented in this thesis aimed at building a basis towards the elaboration of bionic proteins, by proving that such proteomimetics can be used to build novel 3-dimensional constructs. 3-O-alkylated and N-alkylated oligobenzamides with complementary charged side-chains were designed to produce self-assembling foldamers. The synthesis and conformational study of dimers and trimers is reported in Chapter 2. This forms the groundwork towards generating proteomimetic-based coiled coils. An Affimer is a non-antibody-based scaffold, used in tandem with phage display. A small library of biotinylated N-alkylated proteomimetic inhibitors of p53/hDM2 was screened against an Affimer library. The investigation of the Affimer/foldamer interactions are reported in Chapter 3. Taken together, these results demonstrate that aromatic oligoamides are suitable building blocks for producing non-natural peptide sequences in order to generate bionic proteins.