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Inhibiting the protein-protein interaction of B-cell lymphoma 6 using genetically selected cyclic peptide inhibitors

Inhibiting the protein-protein interaction of B-cell lymphoma 6 using genetically selected cyclic peptide inhibitors
Inhibiting the protein-protein interaction of B-cell lymphoma 6 using genetically selected cyclic peptide inhibitors
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.
University of Southampton
Osher, Eliot
bcaf2f72-05de-41b2-aa0d-995f4c66d8f0
Osher, Eliot
bcaf2f72-05de-41b2-aa0d-995f4c66d8f0
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2

Osher, Eliot (2017) Inhibiting the protein-protein interaction of B-cell lymphoma 6 using genetically selected cyclic peptide inhibitors. University of Southampton, Doctoral Thesis, 275pp.

Record type: Thesis (Doctoral)

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.

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Eliot Osher thesis Final - Version of Record
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Published date: May 2017

Identifiers

Local EPrints ID: 415378
URI: http://eprints.soton.ac.uk/id/eprint/415378
PURE UUID: 76178406-b499-4acb-ada2-e32b406ce0bf
ORCID for Ali Tavassoli: ORCID iD orcid.org/0000-0002-7420-5063

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Date deposited: 08 Nov 2017 17:30
Last modified: 15 Sep 2020 04:01

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Contributors

Author: Eliot Osher
Thesis advisor: Ali Tavassoli ORCID iD

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