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Title: An integrated approach to the discovery of inhibitors of protein-protein interactions
Author: Burslem, George McEwan
ISNI:       0000 0004 5363 6854
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2015
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Protein-protein interactions present challenging targets for therapeutic intervention with enormous potential for modulating biological pathways, particularly in the field of oncology. Two α-helix mediated protein-protein interactions of interest, hypoxia inducible factor-1α (HIF-1α)/p300 and eukaryotic initiation factor 4E (eIF4E) /eIF4G are introduced and their known inhibitors discussed in Chapter 1. Initially, biophysical assays for both interactions were developed and the binding requirements between peptides derived from helix donor components (HIF-1α and eIF4G) to their protein counterparts (p300 and eIF4E respectively) were investigated. This information was used to develop competition assays capable of identifying inhibitors and provided important insight for the rational design of inhibitors. Subsequently, a computational approach, described in Chapter 3, to inhibitor discovery was applied to both targets, using both docking and pharmacophore modelling. Several series of compounds were purchased or prepared and screened as inhibitors. The development of a synthetic route to a novel scaffold is described providing a weak small molecule inhibitor. In parallel, a proteomimetic approach to inhibitor design was employed, using sequence based rational design, drawing on the knowledge gained in Chapter 2. By mimicking a key helical region of HIF-1α, the interaction with p300 can be disrupted, as discussed in Chapter 4. Additionally, new methods for the preparation of oligobenzamide helix mimetics were investigated allowing the preparation of challenging targets, late stage functionalization and the preparation of oligobenzamide/peptide hybrids. Overall, this thesis provides an introduction to two therapeutically relevant interactions, provides biophysical assays for the identification of inhibitors and discloses the first biophysically characterised inhibitors of the HIF-1α/p300 interaction.
Supervisor: Wilson, Andrew J. ; Nelson, Adam Sponsor: EPSRC ; AstraZeneca
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available