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Control of peptide secondary structure: photomodulation of peptide a-helicity in the apoptosis signalling pathway.

Taylor, Nicholas John. 2008. Control of peptide secondary structure: photomodulation of peptide a-helicity in the apoptosis signalling pathway. PhD Thesis, Cardiff University.

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Short peptides have been designed and synthesised based on the N-terminus of the p53 tumour suppressor. The crosslinking of these peptides with a thiol-reactive azobenzene crosslinker, optimised for water solubility, builds on previous research that has demonstrated the effective use of this chemical crosslinker in the regulation of a helical peptide structure. Both the crosslinked and uncrosslinked peptides were reported to bind Hdm-2 with high affinity when compared to the wild-type peptide and the isomeric conformation of the attached crosslinker was reported to influence Hdm-2 binding. Although the extent of binding affinity change through crosslinker conformational switching was not as high as intended, this low degree of structural control contributed to the hypothesis that the strength of the peptide interactions with Hdm-2 is enough to overcome the conformational constraints imposed by the crosslinker and that the extent of secondary structure change upon photoswitching may be enhanced by engineering peptides to bind Hdm-2 though with a reduced affinity. The synthesis of Hdm-2 mutants designed to possess a reduced affinity for p53 further supported this proposal. The design of Hdm-2 binding peptides based on a polyalanine scaffold was explored, since polyalanine forms a stable a-helix. The substitution of alanine residues in the appropriate positions respective to one-another with key p53 residues critical to Hdm-2 binding in addition to cysteine residues to enable the attachment of the azobenzene crosslinker led to the development of peptides with Hdm-2 binding affinities comparable to wild-type p53.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Chemistry
Subjects: Q Science > QD Chemistry
ISBN: 9781303197062
Date of First Compliant Deposit: 30 March 2016
Last Modified: 12 Feb 2016 23:12

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