Design, synthesis and conformational analysis of multi-facial helix mimetics
File(s)
Author(s)
Flack, Theo
Type
Thesis
Abstract
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.
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.
Version
Open Access
Date Issued
2019-01
Date Awarded
2019-04
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Barnard, Anna
Tate, Edward
Sponsor
Engineering and Physical Sciences Research Council
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)