Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/128465
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dc.contributor.advisorAbell, Andrew-
dc.contributor.advisorWegener, Kate-
dc.contributor.advisorGeorge, Jonathan-
dc.contributor.authorKeeling, Kelly Lee-
dc.date.issued2018-
dc.identifier.urihttp://hdl.handle.net/2440/128465-
dc.description.abstractThis thesis discusses the design and production of peptides with side chain linkers that are intended to bind to the F3 domain of talin. The talin F3 domain was targeted as it is involved in the activation of integrin membrane proteins present in platelets. The over activation of these integrins can result in clotting within the blood vessels causing heart disease, however, current medication targeting integrin have negative side effects. The design and synthesis of short peptides based on the sequence of the β3 integrin tail that binds to the F3 domain of talin is presented. The binding affinity of peptides to the talin F3 domain was tested using NMR titrations to reveal the ideal location for the linker in the production of potential therapeutics which target integrin activation. Side chain linked peptides with high helical content have previously been shown to improve binding affinity. This drove investigation of side chain constrained peptides to increase their helical content, and thus, their binding affinity to talin F3 domain and cellular uptake. It is demonstrated that side chain linkers are effective in stabilising the helical structure of the short peptides. When incorporated in the β3 integrin sequence in specific locations, lactam linkers improved binding affinity of these peptides to the talin F3 domain. Additionally, all-hydrocarbon and triazole linkers enhanced the peptide’s cellular uptake when compared to the native peptide of this sequence. The position and type of side chain linkers were investigated. The result of which showed that the position of the linker had a significant impact on the binding affinity to talin. The lactam linker between residues in positions 725 and 729 created a peptide (7) with the highest binding affinity. The cell penetration of peptides with different linker types was tested using NIH 3T3 mouse cells, and HEK298 cells. A number of side chain linkers were tested with the triazole linker producing the most α-helical peptide, and the all-hydrocarbon linker producing peptides with the greatest cellular uptake.en
dc.language.isoenen
dc.subjectPeptidesen
dc.subjectconstraineden
dc.subjectside chain linkeden
dc.subjectlinkeren
dc.subjectstapleden
dc.subjectlactamen
dc.subjecttriazoleen
dc.subjectall-hydrocarbonen
dc.subjectperfluoroarylen
dc.subjectintegrinen
dc.subjecthelicityen
dc.subjecttalin inhibitoren
dc.titleA study on side chain linked peptides, toward the development of talin inhibitors using β3 integrin peptide analoguesen
dc.typeThesisen
dc.contributor.schoolSchool of Physical Sciencesen
dc.provenanceThis electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legalsen
dc.description.dissertationThesis (Ph.D.) -- University of Adelaide, School of Physical Sciences, 2018en
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