Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1990-02-12
1991-12-31
Doll, John
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 3, 514 21, 530303, 530324, A61K 3736, C07K 710, C07K 740
Patent
active
050772767
DESCRIPTION:
BRIEF SUMMARY
This invention relates to growth factors, related compounds and their use.
Insulin-like growth factor-1, a somatomedin, is a small protein that has been shown to stimulate growth of a wide range of mammalian cells in culture. Human IGF-1 (hIGF-1) has been purified to homogeneity from human serum and its complete amino acid sequence established. The serum mediator of growth hormone action, somatomedin C, has been shown to have an identical sequence to hIGF-1 so that these two are now considered as being synonymous. The amino acid sequence established for hIGF-1 beginning with the N-terminal glycine is: ##STR1##
IGF-1 levels in serum correlate positively with growth rates in boys during adolescence and negatively with the degree of growth hormone deficiency in growth-retarded subjects, and to both growth rate and eventual size in mice transfected with growth hormone genes. These findings, indirectly linking IGF-1 concentrations with growth rates and. supported by more direct evidence that administration of IGF-1 leads to restoration of growth rates in hypopituitary (growth hormone deficient) rats or mice and to increased growth rates in normal mice, have lead to the interpretation that IGF-1 might usefully be applied: (1) in humans to treat growth hormone deficiencies; (2) in farm animals to increase growth rates and enhance food conversion efficiency. It is further suggested, mostly by analogy with research on growth hormone or anabolic steroids, that administration of IGF-1: (3) may suppress the loss of body protein in severe human catabolic states such as following burns, infection or other trauma; (4) may alter the distribution of tissue to increase the muscle content and decrease the fat content in the body.
The result of the above inferences is that there is a commercial demand for IGF-1 for use in animal growth trials and clinical investigations. However, only milligram amounts of hIGF-1, for example, are available by purification of tonnes of human serum protein.
Accordingly, it is an object of the present invention to overcome, or at least alleviate, one or more of the difficulties related to the prior art.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1. Effects of des3-IGF-1 and IGF-1 on DNA synthesis in cultured L6 myoblasts. Values are expressed relative to the percentage stimulation achieved by 10% fetal bovine serum in parallel cultures.
FIG. 2. Effects of des3-IGF-1 and IGF-1 on protein synthesis is cultured L6 myoblasts. Values are expressed as the percentage stimulation above the rate obtained in growth factor-free media.
FIG. 3. Effects of des3-IGF-1 and IGF-1 on protein breakdown in cultured L6 myoblasts. Values are expressed as a percentage of the maximal inhibitory response achieved.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly in a first aspect there is provided a peptide analogue of mammalian insulin-like growth factor-1 wherein from 1 to 5 amino acid residues are absent from the N-terminal, preferably in a biologically pure form.
Preferably, the peptide is a bovine or human insulin-like growth factor-1 analogue.
More preferably, the peptide analogue has an N-terminal structure selected from
Pro-glu-thr-leu-cys-gly-ala-glu-leu-val-asp-ala-leu-gln-phe-val-cys-gly-asp -arg-gly-phe-tyr-phe-asn-lys-pro-thr-gly-,
Glu-thr-leu-cys-gly-ala-glu-leu-val-asp-ala-leu-gln-phe-val-cys-gly-asp-arg -gly-phe-tyr-phe-asn-lys-pro-thr-gly-,
Thr-leu-cys-gly-ala-glu-leu-val-asp-ala-leu-gln-phe-val-cys-gly-asp-arg-gly -phe-tyr-phe-asn-lys-pro-thr-gly-,
Leu-cys-gly-ala-glu-leu-val-asp-ala-leu-gln-phe-val-cys-gly-asp-arg-gly-phe -tyr-phe-asn-lys-pro-thr-gly-, or
Cys-gly-ala-glu-leu-val-asp-ala-leu-gln-phe-val-cys-gly-asp-arg-gly-phe-tyr -phe-asn-lys-pro-thr-gly-
By the term "biologically pure form" as used herein in the specification and claims we mean a product from which substantially all impurities or contaminants having biological activity have been eliminated.
"Dose-response curves for the compound destripeptide bovine IGF-1 (des3-IGF-1) and bovine IGF-1 (IGF-1) are compared in three separate assays
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Bagley Christopher J.
Ballard Francis J.
Francis Geoffrey L.
Wallace John C.
Chan Christina
Doll John
Gropep Pty Ltd
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