dc.contributor.advisor |
Sarojini, V |
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dc.contributor.author |
Cameron, Alan |
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dc.date.accessioned |
2017-12-17T20:49:53Z |
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dc.date.issued |
2017 |
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dc.identifier.uri |
http://hdl.handle.net/2292/36755 |
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dc.description.abstract |
A variety of cyclic tetrapeptides (CTPs) natural products with a diverse range of bioactivities exist, however, their synthesis still remains challenging. Asperterrestide A (Figure I) is a CTP isolated in 2013 from a marine-derived Aspergillus terreus fungus and is composed entirely of non-protein amino acids. Furthermore, this CTP possesses one 2-aminobenzoic acid (2- Abz residue which is known to have a variety of turn inducing properties in synthetic peptides but can make for very challenging syntheses. This peptide demonstrated cytotoxicity towards human carcinoma cell lines and antiviral activity against influenza virus. The work described in this thesis presents development of synthetic strategy towards cyclic 2-Abz containing CTP derivatives of asperterrestide A. The solution phase cyclisation protocol presented yields CTPs from the linear precursors, prepared by SPPS, with near quantitative conversions. A large library of both linear and cyclic analogues were synthesised for both biological and structural evaluations. However, synthesis of the linear precursor to natural asperterrestide A could not be achieved due to trouble forming the peptide bond between 3-phenylserine and 2-Abz (Figure I). This library, although 2-Abz containing, was devoid of the 3-phenylserine residue, instead replaced with a variety of aromatic or hydroxylated residues. Biological evaluation found one analogue to demonstrate moderate cytotoxicity to HCT116 cells with an IC50 of 34.5 μM. Structural analysis of the analogue library lead to the crystal structure of one linear and one cyclic peptide being solved along with additional calculated structures based on NMR restraints. The crystal structure of linear peptide 1 (Figure II) demonstrated a novel β-turn geometry stabilised by a series of three hydrogen bonds. A similar geometry was observed by solution structure calculation. This novel β-turn framework was incorporated into the synthesis of five proposed β-hairpin peptides. A hydrophobic β-hairpin peptide provided proof of principle implementing this framework. The four additional hairpin peptides, two of which were cyclic analogues of tyrocidine A and two of which were de novo designed linear compounds, provided both linear and cyclic antimicrobial peptides with high potency (low μM MIC) against Gram positive and Gram negative bacterial pathogens. Transmission electron microscopy (TEM) revealed membrane lysis to play an important role in the antimicrobial peptides (AMPs) mode of action. Furthermore the compounds were found to display synergistic antifungal activity with Amphotericin B, providing nanomolar range MIC values. |
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dc.publisher |
ResearchSpace@Auckland |
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dc.relation.ispartof |
PhD Thesis - University of Auckland |
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dc.relation.isreferencedby |
UoA99265040712802091 |
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dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
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dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
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dc.rights.uri |
http://creativecommons.org/licenses/by-nc-sa/3.0/nz/ |
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dc.title |
Structure Based Design, Synthesis and Biological Evaluations of Cyclic Tetrapeptides, β-turn Scaffolds and Antimicrobial β-Hairpins |
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dc.type |
Thesis |
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thesis.degree.discipline |
Chemical Sciences |
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thesis.degree.grantor |
The University of Auckland |
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thesis.degree.level |
Doctoral |
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thesis.degree.name |
PhD |
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dc.rights.holder |
Copyright: The author |
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dc.rights.accessrights |
http://purl.org/eprint/accessRights/OpenAccess |
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pubs.elements-id |
719350 |
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pubs.org-id |
Science |
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pubs.org-id |
Science Research |
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pubs.org-id |
Maurice Wilkins Centre |
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pubs.record-created-at-source-date |
2017-12-18 |
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dc.identifier.wikidata |
Q111963460 |
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