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An Integrated Approach to the Discovery of Inhibitors of Protein-Protein Interactions

Burslem, George McEwan (2015) An Integrated Approach to the Discovery of Inhibitors of Protein-Protein Interactions. PhD thesis, University of Leeds.

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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.

Item Type: Thesis (PhD)
Keywords: Protein-Protein Interactions, Proteomimetics, helix mimetics, inhibitors
Academic Units: The University of Leeds > Faculty of Maths and Physical Sciences (Leeds) > School of Chemistry (Leeds)
The University of Leeds > University of Leeds Research Centres and Institutes > Astbury Centre for Structural Molecular Biology (Leeds)
Depositing User: George M Burslem
Date Deposited: 08 Jul 2015 10:36
Last Modified: 08 Jul 2015 10:36
URI: http://etheses.whiterose.ac.uk/id/eprint/9348

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