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Title: Design, synthesis and delivery of peptide-based systems
Author: Webster, Alexandra Margaret
ISNI:       0000 0004 7226 6254
Awarding Body: Durham University
Current Institution: Durham University
Date of Award: 2018
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Peptide-based therapeutics have been an active area of research for a number of years. They have been found applications as drug-delivery agents, anticancer therapies and as antibiotics, the latter of which is particularly notable when set against a present-day backdrop of the increasing problem of antibiotic resistance. However, the use of peptides is still limited as they suffer from poor bioavailability as a result of their vulnerability to proteolytic degradation. Peptoids are a class of peptidomimetics which represent a potential proteolytically stable alternative to peptides. Chapter 1 introduces peptoids, common methods of their synthesis and their potential therapeutic applications. The challenges associated with controlling peptoid secondary structure are also discussed, along with commonly seen methods of imposing conformational rigidity. Chapter 2 details our attempts to address this problem by synthesising a library of biaryl-containing cyclic peptoids which represent novel peptoid scaffolds. In Chapter 3, we synthesise the active domain (p15) of the known anticancer peptide CIGB-300 along with three stapled analogues on which binding assays can be carried out. In Chapter 4, we synthesise six cell-penetrating peptoids (CPPos) which have previously been reported to localise in mitochondria. Onto these peptoids we conjugated the known anticancer peptide D-KLA and show the ability of these peptoids to increase proapoptotic activity. Flow cytometry and confocal microscopy is then used to demonstrate mitochondrial localisation of the most active peptide-peptoid hybrid, KLA-CPPo6. Having shown the ability of CPPos to transport biologically active cargo, we then conjugate the p15 peptide, previously introduced in Chapter 3, to the six CPPos in preparation for the evaluation of their anticancer activity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available