ITEM VIEW

Structure-function relationships of bolaamphiphilic peptides and peptide hybrids

dc.contributor.advisorSanderson, R. D.
dc.contributor.authorMartari, Marco
dc.contributor.otherUniversity of Stellenbosch. Faculty of Science. Dept. of Chemistry and Polymer Science.
dc.date.accessioned2008-02-06T10:30:16Zen_ZA
dc.date.accessioned2010-06-01T08:13:56Z
dc.date.available2008-02-06T10:30:16Zen_ZA
dc.date.available2010-06-01T08:13:56Z
dc.date.issued2006-12
dc.identifier.urihttp://hdl.handle.net/10019.1/1160
dc.descriptionThesis (PhD (Chemistry and Polymer Science)--University of Stellenbosch, 2006.
dc.description.abstractSynthetic peptides derived from the active core of a natural antimicrobial peptide were used as a template for the design of novel bolaamphiphilic peptides and hybrid molecules. The amphiphilic character of the original compounds was modified by using non-natural amino acids (AAs) – such as ω-AA – and varying the hydrophobic content. The outcomes of these modifications were studied focusing on structural and biological properties. Because of the bolaamphiphilic character, the alternation of polar and non-polar AAs and the use of hydrophobic AAs such as tyrosine and leucine, these novel molecules were designed to undergo self-assembly in response to certain stimuli (e.g. a pH increase). This significant property was investigated by means of different tools, such as fluorescence measurements, electron microscopy (EM), Fourier transform infrared spectroscopy (FT-IR) and circular dichroism (CD). By using fluorescence it was possible to determine the critical aggregation concentration (CAC) of the new compounds. Differences in amino acid composition, which were reflected into diverse secondary structures and hydrophobicity (H), resulted in different CAC values and aggregation profiles. The data were consistent with the literature and showed that (i) the aggregation of these basic compounds was triggered by a pH increase, (ii) the use of hydrophobic AA highly augmented the self-assembly tendency while (iii) the presence of proline strongly reduced it. EM revealed the morphology of the peptide assemblies: microtubes and microvesicles were identified and characterised by dimensions of 500 nm to 2 μm. The presence of 3-way junctions and vesicles budding out of the microtubes demonstrated that the self-assembly is a dynamic process. The aggregation was confirmed by FT-IR spectroscopy, by studying the dried peptide assemblies and the significant spectral signs the process left, especially in the amide II envelope. The relationship between hydrophobicity and self-assembly was expanded by experimentally and theoretically determining the hydrophobic content of the novel bolaamphiphiles. Data from liquid chromatography and computational calculations (two common ways used to determine the hydrophobicity of a given molecule) correlated well with the tendency to self-assemble, as expressed by CAC values. Importantly, some structural parameters (such as the presence of β-turn induced by proline) also showed significant influence on the aggregation, highly limiting the role of the peptides’ hydrophobicity. These novel peptide bolaamphiphiles displayed a very low haemolytic action and retained some antimicrobial activity at high concentrations against both Gram-positive and -negative bacteria. Unfortunately, the activity was greatly reduced at low concentrations, as clearly demonstrated by the use of two antimicrobial tests. The inability to provoke cell lysis was also evident when using liposomes mimicking a negative bacterial membrane. The loss of activity is possibly related to the modifications of the three-dimensional structure caused by the use of ω-AA and proline, which strongly alter the secondary structure. The results of this study were valuable in terms of understanding the relationships between self-assembly and structural parameters, such as AA compositions, hydrophobicity and secondary structure. Possible applications of the synthesised compounds were however limited as a result of the loss of the biological activity at low concentrations.en
dc.format.extent2808877 bytesen_ZA
dc.format.mimetypeapplication/pdfen_ZA
dc.language.isoen
dc.publisherStellenbosch : University of Stellenbosch
dc.subjectBolaamphiphilesen
dc.subjectAggregationen
dc.subjectAntibioticsen
dc.subjectDissertations -- Chemistryen
dc.subjectTheses -- Chemistryen
dc.subjectPeptides -- Synthesisen
dc.subjectAmino acidsen
dc.subjectPeptidesen
dc.titleStructure-function relationships of bolaamphiphilic peptides and peptide hybridsen
dc.typeThesis
dc.rights.holderUniversity of Stellenbosch


Files in this item

Thumbnail
Thumbnail

This item appears in the following Collection(s)

ITEM VIEW