Characterisation and applications of theta-defensins

Conibear, Anne (2014). Characterisation and applications of theta-defensins PhD Thesis, Institute for Molecular Bioscience, The University of Queensland. doi:10.14264/uql.2014.251

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Author Conibear, Anne
Thesis Title Characterisation and applications of theta-defensins
School, Centre or Institute Institute for Molecular Bioscience
Institution The University of Queensland
DOI 10.14264/uql.2014.251
Publication date 2014
Thesis type PhD Thesis
Supervisor David J. Craik
K. Johan Rosengren
Total pages 101
Language eng
Subjects 0304 Medicinal and Biomolecular Chemistry
0601 Biochemistry and Cell Biology
Abstract/Summary Peptides and proteins can interact with high specificity and affinity, making peptides promising molecules for the development of therapeutic agents. Head-to-tail cyclic peptides are abundant in nature and have the additional advantage of being remarkably stable to degradation. One such class of head-to-tail cyclic peptides is the θ-defensins, which form part of the innate immune system of some species of primates. θ-Defensins comprise 18 amino acid residues and three disulfide bonds in a parallel arrangement termed the ‘cyclic cystine ladder’. Their antibacterial and antiviral activities have been widely studied with a view to using them as antimicrobial agents. However, the structural features that give rise to the stability of θ-defensins are not well understood and their potential as stable scaffolds for peptide drug design has not yet been explored. In this work, native and modified θ-defensins were designed and synthesized using solid phase peptide synthesis and then characterised by nuclear magnetic resonance spectroscopy and biological activity assays. The aim was to determine the structural features that give rise to the stability of θ-defensins and to explore how these features might be applied to the design of stable peptide scaffolds. The work described in this thesis demonstrates that θ-defensins are amenable to chemical synthesis and have a well defined β-sheet structure that is constrained by the cyclic cystine ladder motif. The disulfide bonds in the cyclic cystine ladder have a role in the structure and stability of θ-defensins but are not required for their antibacterial or membrane-binding activity. Furthermore, the potential of θ-defensins as a scaffold for peptide drug design is demonstrated in showing that θ-defensins can be designed with a specific non-native bioactivity and still remain stable and structured. The characterisation of θ-defensins described in this thesis contributes to our understanding of stable naturally occurring cyclic peptides and illustrates the value of chemical synthesis and nuclear magnetic spectroscopic techniques for the study of peptides. Moreover, the cyclic cystine ladder has been established as a stable and versatile scaffold for peptide drug design that complements scaffolds based on other classes of cyclic peptides. The development of stable and bioactive peptides should facilitate their application in the treatment of disease and our understanding of biological processes that involve interactions between proteins.
Keyword Peptides
Solid phase peptide synthesis (SPPS)
Nuclear Magnetic Resonance (NMR)
Peptide drug design
Peptide Structure
Cyclic peptides

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Created: Mon, 11 Aug 2014, 11:11:40 EST by Anne Conibear on behalf of Scholarly Communication and Digitisation Service