Brimble, MACornish, JAmso, Zaid2017-03-172017http://hdl.handle.net/2292/32222This thesis focusses on the design, synthesis, and biological evaluation of analogues of the naturally occurring peptides dianthin G and preptin (1-16) for the potential treatment of osteoporosis. The thesis also explores the total chemical synthesis of the bacteriocin glycocin F and analogues along with their evaluation as novel agents for the treatment of bacterial infections. Dianthin G is a cyclohexapeptide natural product obtained from Dianthus superbus, a Chinese medical plant. This peptide was shown to promote osteoblast (bone-forming cell) proliferation in vitro at nanomolar concentrations, and is therefore considered a promising candidate for the treatment of osteoporosis. An Nα-methyl amide bond scan of dianthin G was performed to probe the effect of modifying amide bonds on osteoblast proliferation which resulted in the synthesis of five analogues of dianthin G. Biological evaluation of these analogues showed that the presence of all native amide bonds in the primary sequence of dianthin G is important for osteoblast proliferation activity. In addition, to provide greater structural diversity, a series of dicarba dianthin G analogues was synthesised using ring closing metathesis. Dianthin G and one novel dicarba analogue increased the number of human osteoblasts and importantly they did not increase osteoclast (bone-resorbing cell) differentiation in bone marrow cells. Preptin is a 34-residue pancreatic hormone shown to be anabolic to bone in vitro and in vivo, and is therefore considered a promising candidate for the treatment of osteoporosis. The bone activity of preptin resides within the (1-16) N-terminal fragment. Due to its peptidic nature, the truncated fragment of preptin is enzymatically unstable; however this provides an attractive framework for the creation of stable analogues using peptidomimetic techniques. An alanine scan of preptin (1-16) was undertaken which demonstrated that substitution of Ser at position 3 or Pro at position 14 did not inhibit the proliferative activity of preptin in primary rat osteoblasts. Importantly, the Ser-3 to Ala substitution also showed a significant activity on osteoblast differentiation in vitro and increased the formation of mineralised bone matrix. Additional modifications with non-proteinogenic amino acids at position 3 improved the stability in liver microsomes, but diminished the osteoblast proliferative activity. In addition, to provide greater structural diversity, a series of macrocyclic preptin (1-16) analogues was synthesised using head-to-tail, head-to-side chain macrolactamisation or ring-closing metathesis. However, a detrimental effect on osteoblast activity was observed for all preptin peptides that contained macrocyclisation. Glycocin F is a 43-residue glycopeptide bearing a rare S-linked N-acetylglucosamine (GlcNAc) moiety at position 43 in addition to an O-linked GlcNAc at position 18 and two disulfide bonds. This peptide is a potent bacteriostatic agent, being active against both Gram positive and Gram negative pathogens, and therefore is considered a promising candidate for the treatment of bacterial infections. Native glycocin F was successfully synthesised using a native chemical ligation strategy and then folded into its native structure. In addition, four variants of glycocin F were prepared; three of which contained a single modification in one of the sugar residues, and the other contained D-His at position 27. The synthetic glycopeptides were shown to possess primarily an α-helical secondary structure by circular dichroism spectroscopy. Through biological evaluation, the S-linked GlcNAc moiety was found to be essential for the bacteriostatic effect of glycocin F. In addition, a significant increase in the antibacterial activity was observed upon replacing O-GlcNAc at position 18 with S-GlcNAc, possibly due to the S-glycosidic linkage being more resistant to enzymatic cleavage compared to the O-glycosidic linkage.Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher.https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htmThesisCopyright: The authorhttp://purl.org/eprint/accessRights/OpenAccessQ111963928