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dc.contributor.authorChisholm, Timothy Stewart
dc.date.accessioned2019-09-11
dc.date.available2019-09-11
dc.date.issued2019-09-09
dc.identifier.urihttp://hdl.handle.net/2123/21084
dc.description.abstractPeptides and proteins underpin all biological function. These ubiquitous biomolecules take on a plethora of structural and functional roles in the cell, leading to intensive research efforts into understanding the fundamental nature of these biopolymers and their potential application as therapeutics. Homogeneous samples of peptides and proteins are necessary for such studies, yet many remain inaccessible in useful quantities. The chemical synthesis of these biomolecules is underpinned by ligation chemistry, with native chemical ligation being the most widely used. However, ligation chemistry suffers from two key limitations. First, there is a paucity of ligation techniques that have been applied in a scalable manner. Second, a significant portion of hydrophobic polypeptides remain inaccessible by ligation chemistry due to their poor aqueous solubility. This thesis outlines the development of novel technologies for the synthesis of peptides and proteins, focusing on overcoming these two limitations. In Chapter 2 the scalability of NCL is addressed through the application of flow chemistry to the synthesis of polypeptide therapeutics. This platform is used for the efficient preparation of the HIV fusion inhibitor enfuvirtide 45-fold faster than comparable batch methods. The diagnostic agent somatorelin is also rapidly synthesised via the largest-scale ligation in the literature, yielding over 100 mg of purified product. Chapter 3 details the development of reductive diselenide-selenoester ligation (rDSL) methodology. This rDSL reaction is the first non-templated ligation method to operate at nanomolar concentrations. This protocol allowed for the efficient synthesis of tesamorelin, a lipidated therapeutic. The methods developed herein have therefore directly addressed two critical problems in peptide chemistry, allowing ligations to be performed in a scalable manner and at low concentrations.en_AU
dc.publisherUniversity of Sydneyen_AU
dc.publisherFaculty of Scienceen_AU
dc.publisherSchool of Chemistryen_AU
dc.rightsThe author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.en_AU
dc.subjectchemistryen_AU
dc.subjectpeptideen_AU
dc.subjectligationen_AU
dc.subjectdilutionen_AU
dc.subjectseleniumen_AU
dc.titleDevelopment of Novel Technologies for Efficient Peptide and Protein Synthesisen_AU
dc.typeMasters Thesisen_AU
dc.type.pubtypeMaster of Philosophy (Science)en_AU
dc.description.disclaimerAccess is restricted to staff and students of the University of Sydney . UniKey credentials are required. Non university access may be obtained by visiting the University of Sydney Library.en_AU


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