Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1989-08-24
1992-11-17
Cashion, Jr., Merrell C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530324, 930120, A61K 3702, C07K 500
Patent
active
051643707
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 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: -asp-arg-gly-phe-tyr-phe-asn-lys-pro-thr-gly-tyr-gly-ser-ser-ser-arg-arg-al a-pro-gin-thr-gly-ile-val-asp-glu-cys-cys-phe-arg-ser-cys-asp-leu-arg-arg-l eu-glu-met-tyr-cys-ala-pro-leu-lys-pro-ala-lys-ser-ala-
Bovine IGF-1 and porcine IGF-1 have identical sequences.
Using the conventional numbering system of the N-terminal glycine being residue #1 and the C-terminal alanine residue #70, ovine and chicken IGF-1 differ from human IGF-1 only as follows:
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 rats, 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, increase the relative proportion of muscle and enhance food conversion efficiency. It is further suggested 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 improve wound healing in human subjects as well as in animals. IGF-1 can also be used to (5) support the growth of cells in culture.
The result of the above inferences is that there is a commercial demand for IGF-1 for use in animal trials, clinical investigations and for cell culture. However, only milligram amounts of hIGF-1, for example, are available by purification of tonnes of human serum protein and yields from recombinant DNA methods remain low.
Insulin-like growth factor-2 (IGF-2) like IGF-1, is a small protein that has been shown to stimulate growth of cells in culture. In most cases, these biological effects occur following interaction of IGF-2 with the same cellular receptor as is involved in IGF-1 actions. The amino acid sequence established for human IGF-2 (hIGF-2) beginning with the N-terminal alanine is shown below. Upper case letters have been used to indicate the amino acids equivalent to the N-terminal 5 amino acids of hIGF-1: -val-cys-gly-asp-arg-gly-phe-tyr-phe-ser-arg-pro-ala-ser-arg-val-ser-arg-ar g-ser-arg-gly-ile-val-glu-glu-cys-cys-phe-arg-ser-cys-asp-leu-ala-leu-leu-g lu-thr-tyr-cys-ala-thr-pro-ala-lys-ser-glu
Using the conventional numbering system of the N-terminal alanine being residue #1 and the C-terminal glutamic acid being residue #67, bovine, ovine, porcine and chicken IGF-2 differ from human IGF-2 only as follows: ; gly.sup.33 ; asn.sup.35 ; asn.sup.36 ; ile.sup.39 ; asn.sup.40
It has been disclosed (see PCT/AU87/00246 to applicants) that compounds corresponding to IGF-1 but lacking one to five, preferably three amino acid residues from the N-terminal cf the molecule can exhibit a substantial increase in biological potency compared with the more complete compounds.
For example, the compound destripeptide bIGF-1 but lacking the amino acid residues gly, pro and glu from the N-terminal, is effective in inhibiting protein breakdown and stimulating both protein synthesis and DNA synthesis in cellular systems at concentrations between 4 and 50 fold lower than required for entir
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Ballard Francis J.
Wallace John C.
Wells Julian R. E.
Cashion Jr. Merrell C.
Celsa B.
GroPep Pty. Ltd.
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