Synthesis and properties od some novel cyclic peptides with incorporation of some novel amino acids
Synthesis and properties od some novel cyclic peptides with incorporation of some novel amino acids
Transforming growth factor-α(TGF-α) is a member of a family of homologous polypeptides which bind to the epidermal growth factor receptor (EGF-R) and is responsible for cell proliferation. TGF-α contains 50 amino acids and is comprised of three loops α, β and γ, which are each formed via a disulphide bridge between two cysteines. Previous analogues of EGF and TGF-α have been tested for activity in an attempt to identify the residue(s) involved at the receptor/growth factor interface, thus enabling the development of agonists or antagonists. This thesis discusses the novel synthetic routes to a series of amino acids, their assembly into a set of linear peptides using fmoc solid phase peptide synthesis (SPPS) and the formation of the corresponding cyclic peptides. The basic structures of the amino acids were prepared by Diels-Alder methodology, and subsequently converted to the corresponding amino acids. The four linear peptides synthesized were the β-loop of TGF-α (residue 21 to 32), and three analogues of the β-loop of TGF-α.
These three peptide analogues have residue 30(L-proline) replaced by D-proline or (1R,3R,4S)-2-azabicyclo-(2,2,1)-heptane-3-carboxylic acid or (1S,3S,4R)-2-azabicyclo-(2,2,1)-heptane-3-carboxylic acid. The four linear peptides were cyclised via formation of a disulphide bridge between the two cysteine units. The linear and cyclic peptides were purified by reverse phase high performance liquid chromatography (RP-HPLC) and proof of structure was by nuclear magnetic resonance (N.M.R.), mass spectrometric data, amino acids analysis and circular dichroism. The N.M.R. experiments using both 1 and 2D (TOCSY and ROESY) methods were carried out and confirmed the amino acid residues, the sequential linkages, and indicated any possible conformational properties of both the linear and cyclic peptides. Biological testing, which involved a mitogenesis assay test of the detection of EGF-receptor tyrosine phosphorylation was carried out on both the linear and cyclic peptides. (DX 184, 255)
University of Southampton
1994
Sargood, Karen Jane
(1994)
Synthesis and properties od some novel cyclic peptides with incorporation of some novel amino acids.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
Transforming growth factor-α(TGF-α) is a member of a family of homologous polypeptides which bind to the epidermal growth factor receptor (EGF-R) and is responsible for cell proliferation. TGF-α contains 50 amino acids and is comprised of three loops α, β and γ, which are each formed via a disulphide bridge between two cysteines. Previous analogues of EGF and TGF-α have been tested for activity in an attempt to identify the residue(s) involved at the receptor/growth factor interface, thus enabling the development of agonists or antagonists. This thesis discusses the novel synthetic routes to a series of amino acids, their assembly into a set of linear peptides using fmoc solid phase peptide synthesis (SPPS) and the formation of the corresponding cyclic peptides. The basic structures of the amino acids were prepared by Diels-Alder methodology, and subsequently converted to the corresponding amino acids. The four linear peptides synthesized were the β-loop of TGF-α (residue 21 to 32), and three analogues of the β-loop of TGF-α.
These three peptide analogues have residue 30(L-proline) replaced by D-proline or (1R,3R,4S)-2-azabicyclo-(2,2,1)-heptane-3-carboxylic acid or (1S,3S,4R)-2-azabicyclo-(2,2,1)-heptane-3-carboxylic acid. The four linear peptides were cyclised via formation of a disulphide bridge between the two cysteine units. The linear and cyclic peptides were purified by reverse phase high performance liquid chromatography (RP-HPLC) and proof of structure was by nuclear magnetic resonance (N.M.R.), mass spectrometric data, amino acids analysis and circular dichroism. The N.M.R. experiments using both 1 and 2D (TOCSY and ROESY) methods were carried out and confirmed the amino acid residues, the sequential linkages, and indicated any possible conformational properties of both the linear and cyclic peptides. Biological testing, which involved a mitogenesis assay test of the detection of EGF-receptor tyrosine phosphorylation was carried out on both the linear and cyclic peptides. (DX 184, 255)
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Published date: 1994
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Local EPrints ID: 458494
URI: http://eprints.soton.ac.uk/id/eprint/458494
PURE UUID: 1add4b39-8a82-4c32-ab69-aab916784ebd
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Date deposited: 04 Jul 2022 16:50
Last modified: 04 Jul 2022 16:50
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Author:
Karen Jane Sargood
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