Use this URL to cite or link to this record in EThOS:
Title: Development and evaluation of novel hydrocarbon stapled peptidomimetics with future application to bionic proteins
Author: Yeo, David James
ISNI:       0000 0004 5348 6227
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2014
Availability of Full Text:
Access from EThOS:
Access from Institution:
Hydrocarbon stapling is a method of constraining a short polypeptide through the incorporation of alkenyl alanine unnatural amino acids, which are metathesised during peptide synthesis to afford a covalent crosslink on one face of the peptide. The purpose of 'stapling' is to improve the therapeutic properties of a peptide by improving transport properties and resistance to proteolysis. Stapling also reduces the conformational plasticity of a peptide, which in turn, should improve the potency of the crosslinked peptide with its binding partner. Alkenyl glycine ('monosubstituted') derivatives of amino acids have been previously synthesised, but overlooked for peptide stapling experiments. This project investigated the utility of monosubstituted amino acids as surrogates for hydrocarbon stapling with a therapeutically relevant family of proteins, the apoptosis regulator Bcl-2 family and p53 proteins. This led onto an investigation of the foundations of hydrocarbon stapling, to assess the extent that hydrocarbon stapling modulates potency through various biophysical and structural experiments. Hydrocarbon stapled peptides are classified as peptidomimetics within the field of foldamers, which aims to construct scaffolds from synthetic oligomers which can replicate the three dimensional topography and functionality of native proteins. Since the de novo design of synthetic proteins is out of reach, regions of proteins with distinct architecture have been replaced with mimetics to afford semi-synthetic proteins in a technique described as 'protein prosthesis'. The project also aimed to chemically synthesise a protein with four distinct helical regions, colicin immunity protein Im7, with the view to replace one of the helical regions with a stapled peptide or an oligobenzamide helix mimetic to afford a semi-synthetic protein to add to the growing field of secondary and tertiary structure mimetics.
Supervisor: Wilson, Andrew J. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available