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The development of cyclic peptide inhibitors of hypoxia-inducible factors

The development of cyclic peptide inhibitors of hypoxia-inducible factors
The development of cyclic peptide inhibitors of hypoxia-inducible factors
Hypoxia inducible factors (HIFs) are transcription factors that act as the master regulators of oxygen homeostasis. Diseases such as cancer can disrupt this homeostasis leading to areas with low environmental oxygen (hypoxia) especially in tumour cores. HIFs control the expression of hundreds of genes involved in processes such as metabolism, erythrogenesis, angiogenesis and pH regulation, all of which aid in the adaptation of cells to survive in hypoxic conditions. In the case of cancer this adaptation promotes the progression and metastasis of the disease, leading to HIF becoming a prominent target for therapeutic intervention. In this work, the structure activity relationship of the cyclic peptide HIF inhibitor cyclo-CLLFVY has been explored. A series of derivatives were synthesised via the incorporation of unnatural amino acids, which led to the development of a new lead peptide that was shown to bind to HIF with a 30-fold greater affinity than cyclo-CLLFVY. The improved peptide leads have been used in the development of several new in vitro assays for the quantification of HIF binding and inhibition of HIF activity. Determination of the structural basis of cyclo-CLLFVY binding was also attempted via an x-ray crystallographic approach, which led to the development of a novel HIF structure.
University of Southampton
Gardner, Reece
e09aff5b-e46b-4248-8f25-b7581d023b47
Gardner, Reece
e09aff5b-e46b-4248-8f25-b7581d023b47
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2

Gardner, Reece (2020) The development of cyclic peptide inhibitors of hypoxia-inducible factors. Doctoral Thesis, 201pp.

Record type: Thesis (Doctoral)

Abstract

Hypoxia inducible factors (HIFs) are transcription factors that act as the master regulators of oxygen homeostasis. Diseases such as cancer can disrupt this homeostasis leading to areas with low environmental oxygen (hypoxia) especially in tumour cores. HIFs control the expression of hundreds of genes involved in processes such as metabolism, erythrogenesis, angiogenesis and pH regulation, all of which aid in the adaptation of cells to survive in hypoxic conditions. In the case of cancer this adaptation promotes the progression and metastasis of the disease, leading to HIF becoming a prominent target for therapeutic intervention. In this work, the structure activity relationship of the cyclic peptide HIF inhibitor cyclo-CLLFVY has been explored. A series of derivatives were synthesised via the incorporation of unnatural amino acids, which led to the development of a new lead peptide that was shown to bind to HIF with a 30-fold greater affinity than cyclo-CLLFVY. The improved peptide leads have been used in the development of several new in vitro assays for the quantification of HIF binding and inhibition of HIF activity. Determination of the structural basis of cyclo-CLLFVY binding was also attempted via an x-ray crystallographic approach, which led to the development of a novel HIF structure.

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Reece Gardner Thesis Corrected
Restricted to Repository staff only until 30 November 2023.
Available under License University of Southampton Thesis Licence.
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PTD_Gardner-SIGNED
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More information

Published date: November 2020

Identifiers

Local EPrints ID: 447273
URI: http://eprints.soton.ac.uk/id/eprint/447273
PURE UUID: 8c544d13-3c07-46b2-a0ad-af781a497cab
ORCID for Ali Tavassoli: ORCID iD orcid.org/0000-0002-7420-5063

Catalogue record

Date deposited: 08 Mar 2021 17:31
Last modified: 09 Mar 2021 02:39

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