Studies towards the synthesis of fibronectin-based peptidomimetics.
PhD thesis, University of Glasgow.
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Fibronectin (FN) protein was discovered in the early 1970s by Richard Hynes. Since then this large, multidomain glycoprotein present in the extracellular matrix and in
body fluids has been intensively research, and has been found to play a fundamental role in cell adhesion, cell migration, cell survival, angiogenesis, and other important
biological processes. In recent years the interest in FN has risen; the novel FN isoform, termed Migration Stimulating Factor (MSF) has been cloned and characterized, and new results documenting the involvement of FN and MSF in
wound healing, cancer progression and bacterial metastasis have been presented. The recent findings have shown that MSF’s bioactivities (e.g. stimulation of cell motility, hyaluronan synthesis and angiogenesis) are mediated by the highly conserved amino acid motif Ile-Gly-Asp (IGD), and are mimicked by small synthetic peptides containing this sequence. The aim of this project was to design and synthesize first generation non-peptidic compounds which could mimic the biological activity of MSF (i.e. IGD peptidomimetics).
The second part of this thesis describes the role of FN in bacterial pathogenesis. Staphylococcus aureus is commonly present in the nose and on the skin of one third of all people, and is normally harmless at these sites. However, the microorganism possesses the ability to enter the body, invade cells and cause infection. The mechanism for S. aureus adhesion to, and invasion of, human cells has been
extensively studied. It is now postulated that bacterial invasion is mediated by FN, that acts as a bridge between bacterial proteins adhesins and integrin receptors present on the cell surfaces. The biologically active motif, by which FN mediates its adhesion to bacterium, has not been unambiguously identified. However, the preliminary, unpublished studies point towards a short terapeptide sequence, Gly-Arg-Ile-Ser (GRIS), which is highly conserved within FN. We proposed to elucidate the role of the native GRIS motif by synthesising a small, nonpeptidic molecule,
which could mimic its biological properties and activities.
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