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Development of second generation cyclic peptide inhibitors of hypoxia inducible factors

Development of second generation cyclic peptide inhibitors of hypoxia inducible factors
Development of second generation cyclic peptide inhibitors of hypoxia inducible factors
Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors that function as the master regulators of the cellular response to low oxygen concentrations. HIFs upregulate the expression of genes that promote growth and initiate metabolic changes, which subsequently aid survival and reoxygenation under these conditions. Tumour cores often contain oxygen-depleted regions that exhibit high levels of HIF activity, subsequently triggering this biochemical response. HIF activity is thought to be associated with the aggressive growth, metastasis and greater persistence phenotypes exhibited by such tumours. As such the inhibition of the HIF pathway is considered to be an attractive target in the development of new cancer therapeutics.

This work presents a set of novel cyclic peptide inhibitors of the HIF pathway, which function by disrupting a key protein-protein interaction between the α and β subunits of the HIF heterodimeric transcription factor. These peptides were selected for their ability to inhibit both isoforms of the HIF-α subunit. The affinity of the peptides for each of these was determined and from this, a lead peptide was identified.

The structure-activity relationship of the lead peptide with the protein target has been explored, through use of alanine scanning and incorporation of unnatural amino acid derivatives. This approach has led to the identification of an optimised HIF inhibitor that exhibits a binding affinity below the μM threshold.

A series of in vitro assays to detect HIF dimerization have also been designed and utilised. The effects of the inhibitory peptides on these systems has also been investigated.
University of Southampton
Ball, Andrew Tomas
04031b6f-7446-430b-9494-7561a82600e0
Ball, Andrew Tomas
04031b6f-7446-430b-9494-7561a82600e0
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2

Ball, Andrew Tomas (2018) Development of second generation cyclic peptide inhibitors of hypoxia inducible factors. University of Southampton, Doctoral Thesis, 274pp.

Record type: Thesis (Doctoral)

Abstract

Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors that function as the master regulators of the cellular response to low oxygen concentrations. HIFs upregulate the expression of genes that promote growth and initiate metabolic changes, which subsequently aid survival and reoxygenation under these conditions. Tumour cores often contain oxygen-depleted regions that exhibit high levels of HIF activity, subsequently triggering this biochemical response. HIF activity is thought to be associated with the aggressive growth, metastasis and greater persistence phenotypes exhibited by such tumours. As such the inhibition of the HIF pathway is considered to be an attractive target in the development of new cancer therapeutics.

This work presents a set of novel cyclic peptide inhibitors of the HIF pathway, which function by disrupting a key protein-protein interaction between the α and β subunits of the HIF heterodimeric transcription factor. These peptides were selected for their ability to inhibit both isoforms of the HIF-α subunit. The affinity of the peptides for each of these was determined and from this, a lead peptide was identified.

The structure-activity relationship of the lead peptide with the protein target has been explored, through use of alanine scanning and incorporation of unnatural amino acid derivatives. This approach has led to the identification of an optimised HIF inhibitor that exhibits a binding affinity below the μM threshold.

A series of in vitro assays to detect HIF dimerization have also been designed and utilised. The effects of the inhibitory peptides on these systems has also been investigated.

Text
Andrew Ball thesis final corrected - Version of Record
Restricted to Repository staff only until 31 March 2022.
Available under License University of Southampton Thesis Licence.

More information

Published date: September 2018

Identifiers

Local EPrints ID: 429015
URI: http://eprints.soton.ac.uk/id/eprint/429015
PURE UUID: 4a0469dd-6fcc-4497-bf40-c43db7646668
ORCID for Ali Tavassoli: ORCID iD orcid.org/0000-0002-7420-5063

Catalogue record

Date deposited: 19 Mar 2019 17:30
Last modified: 06 Apr 2019 00:34

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