Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 11 to 14 amino acid residues in defined sequence
Patent
1997-12-11
1999-10-19
Tsang, Cecilia J.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
11 to 14 amino acid residues in defined sequence
530399, 514 14, C07K 700
Patent
active
059690992
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to peptides having growth factor receptor activity, and in particular to peptides which are analogs of Transforming Growth Factor-Alpha (TGFA). The invention further relates to uses of such peptides.
Growth factors represent a group of polypeptides which induce inter alia cell division. TGFA and the closely related Epidermal Growth Factor (EGF) have a role in a number of normal physiological processes such as wound healing.
The sequence and three dimensional structure of both EGF and TGFA have been determined (Campbell et al, Prog. Growth Factor Res. 1989, 1, 13-22). EGF is a 53 amino acid polypeptide (Sequence I.D. No. 1). TGFA is a 50 amino acid polypeptide (Sequence I.D. No. 2) having about 40% homology of residues with EGF. Both peptides are characterised by three well defined loops (denoted A, B and C) and have three intramolecular disulphide bonds.
Several growth factors, including TGFA and EGF, are believed to exert their biological effects via interaction with the Epidermal Growth Factor Receptor (EGF Receptor). The EGF Receptor is a Type 1 receptor tyrosine kinase. The EGF Receptor and its ligands are of interest for their roles in normal physiological processes as well as in hyperproliferative and neoplastic diseases.
A number of studies have been made to establish structure-function relationships within EGF and TGFA so as to be able to design suitable investigative or therapeutic agents (such as EGF Receptor agonists and antagonists). These studies have been made on the well established basis that the sequence of amino acids from which a polypeptide or protein is composed (or primary structure) has a profound effect on its three dimensional (secondary, tertiary and quarternary) structure. The three dimensional structure will in turn affect the function and activity of the polypeptide or protein.
Thus by altering (either randomly or rationally) the number or sequence of amino acids in a peptide, properties such as its kinetics, stability, protease or thermal resistance, specificity and ligand-receptor interactions may be controlled.
Thus in EGF it has been reported that synthetic fragments corresponding to the B-loop bind to the EGF Receptor and have weak mitogenic activity (Komoriyam et al, Proc. Natl. Acad. Sci. USA 1984, 81, 1351). Analogs of the C-loop also have biological activity (Bailie, J. R. et al, Int J, Peptide Protein Res. 1994, 43, 225). Residue 47 (leucine) near the C-terminus of the peptide has also been shown to be important in binding and mitogenesis (Ray, P. et al, Biochemistry 1988, 27, 7289).
In TGFA it has been reported that synthetic peptides corresponding to the B-loop bind only weakly to the EGF Receptor and do not invoke a mitogenic response (see, eg Defeo-Jones, D. et al Mol. Cell. Biol. 1988, 8, 2999-3007). It has also been found that residue 15 (phenylalanine) is an important receptor contact; Mol. Cell. Biol. 1988, 8, 2999-3007.
Unfortunately none of the synthetic peptides reported above have been shown to possess significant potential as EGF Receptor agents. Thus there currently exists a need for novel growth factor analogs (or other growth factor receptor ligands) for use in the investigation or manipulation of growth factor mediated processes and diseases.
The present invention has now provided novel growth factor analogs and methods of preparation of such analogs that address shortcomings of the prior art.
According to a first aspect of the present invention there is provided a peptide comprising an amino acid sequence corresponding to Sequence I.D. No 3 or a sequence wherein the amino acids of Sequence I.D. No 3 are replaced by conservative substitutions or a sequence having 90% homology to either of these peptide sequences characterised in that the amino acid at position 10 of Sequence I.D. No 3 or the sequences conservatively substituted or homologous thereto is a bicyclic proline analog and in that a disulphide bridge is provided between the cysteine residues at positions 1 and 12.
By bicyclic proline analog is meant any azabicycl
REFERENCES:
patent: 4686283 (1987-08-01), Nestor et al.
Acta Chem. Scand. (1992), 46(3), 266-70 Coden: ACHSE7;ISSN: 0904-213X, 1992, XP002002947 Bahr, Josephine et al: Antigenic properties of the second loop of transforming growth factor.alpha. by synthetic peptides.
International Journal of Peptide and Protein Research, vol. 39, No. 5, May(1992,) Copenhagen DK, pp. 464-471, XP002002948 J.P. Tam and X.-Y. Shen: "Efficient approach to synthesis of two-chain asymmetric cysteine analogs of receptor-binding region of transforming growth factor-alpha".
J. Biol. Chem. (1995), 270(36), 21062-7 Coden: JBCHA3:ISSN: 0021-9258, Sep. 8, 1995, XP002002949 Chamberlin, Stephen G. et al: "Constrained peptide analogs of transforming growth factor-.aplha.residues cysteine 21-32 are mitogenically active. Use of proline mimetics to enhance biological potency".
Anderson Derek W.
Chamberlin Stephen G.
Davies Donna E.
Mellor John M.
Richards Nigel G. J.
Delacroix-Muirheid C.
The Secretary of State for Defence
Tsang Cecilia J.
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