Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.729641
Title: Inhibiting the protein-protein interaction of B-cell lymphoma 6 using genetically selected cyclic peptide inhibitors
Author: Osher, Eliot
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2017
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Thesis embargoed until 15 Sep 2020
Access from Institution:
Abstract:
Aberrant expression of the B-cell lymphoma 6 (BCL6) oncoprotein has been associated with a large percentage of diffuse large B-cell lymphoma cases, the most common subset of Non-Hodgkin’s lymphoma. With cancers of this type highly dependent upon combination therapy, there is much desire to find more bioavailable and less cytotoxic treatment options than the current ‘gold’ standard. Here, homo- and heterodimeric protein-protein interaction inhibitors of the Nterminal Bric-a-brac tramtrack broad-complex (BTB) domain of BCL6 have been identified. This was achieved by combining a bacterial reverse two-hybrid system with a split intein based methodology to screen libraries of backbone cyclic peptides. A bacterial reverse two-hybrid system for BTB homodimerisation was constructed, alongside two heterodimeric systems targeting the BCL6 and silencing mediator of retinoic acid and thyroid receptor corepressors. From these three systems a series of cyclic peptide sequences were identified that were found to exhibit inhibitory activity. These cyclic peptides were subsequently synthesised by solid phase peptide synthesis and their activity assessed using a range of in vitro based assays. This research has resulted in the identification of one active cyclic peptide with mid micromolar affinity that has the propensity to disrupt BTB homodimerisation. In contrast, a number of active cyclic peptide inhibitors have been discovered against BTB heterodimerisation with the most potent inhibitors demonstrating corepressor specific activity despite a conserved binding site. These peptides provide a foundation for the future design of more potent inhibitors against BCL6.
Supervisor: Tavassoli, Ali Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.729641  DOI: Not available
Share: