Design, synthesis and conformational analysis of multi-facial helix mimetics

The inhibition of protein-protein interactions using rationally designed molecules is a powerful method for exploring the biological role of these interactions, particularly in the pathogenesis of many common diseases. The most common molecular recognition scaffold in multi-protein complexes is the a-helix and as such numerous helix mimetic designs have been reported.1 However, the majority of these designs have focused of mimicry of a single helical face. Given that many therapeutically relevant interactions are mediated through the binding of multiple helical faces, multi-facial helix mimetics represent a promising method for PPI inhibition.2 This thesis will describe the synthesis and characterisation of an oligoamide scaffold capable of projecting functionality that represents two distinct helical faces. A modular solution-phase synthetic route capabale of incorporating functionality found across all proteinogenic amino acids has been designed. The conformational landscape of the helix mimetics have been extensively studied using both solution- and solid-phase techniques. A series of bifunctional helix mimetics have been designed based on the helical tail of MyosinA (MyoA); a key component of the invasion machinery of Plasmodium parasites. The ability of the mimetics to perturb the motor complex has been established using a cascade of biophysical techniques. In addition, a series of peptide-helix mimetic chimeras have been synthesised by replacing sequential helical turns with topographical mimics. It was established that coupling the native recognition properties of peptides with the enhanced structural and metabolic stability of helix mimetics could potentially permit the assembly of protein-like objects with superior functionality compared to the native peptide and helix mimetics alone. It is anticipated that the approaches presented here will afford translatable designs for peptidomimetics capable of inhibiting a variety of complex PPIs.