Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1996-01-05
1998-09-29
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 18, 530330, A61K 3518, A61K 3736, C07K 1506, C07K 708
Patent
active
058146105
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The invention relates to osteogenic growth oligopeptides which possess stimulatory activity on osteoblastic and fibroblastic cells.
BACKGROUND OF THE INVENTION
It has been established that regenerating marrow induces an osteogenic response in distant skeletal sites and that this activity is mediated by (1985) Calcif. Tissue Int. 37:551;Foldes, J. et al (1989) J. Bone Min. Res. 4:643;Einhorn, T. A. et al (1990) J. Bone Joint Surg. Am. 72:1374;Gazit D., et al (1990) Endocrinology 126:2607;Mueller, M. et al (1991) J. Bone Min. Res. 6:401!. One of these factors, a 14-amino acid osteogenic growth polypeptide (OGP), identical with the C-terminus of 11:1867;European Patent Applications Nos. 89201608.0and 90301862.0!. A histone H4fragment of the formula Tyr-Gly-Phe-Gly- Gly is disclosed in Kharchenko, E. P. et al (1989) Vopr. Med. Khim. 35( 2):106-9and in Kharchenko, E. P. et al (1987) Biull. Eksp. Biol. Med. 103(4):418-20.This peptide demonstrated analgesic and opiod activity.
Synthetic 14-mer osteogenic growth polypeptide (sOGP), identical in structure with the native molecule, has been shown to be a potent stimulator of proliferation of osteoblastic and fibroblastic cells in vitro. This synthetic polypeptide also stimulates osteoblastic cell alkaline phosphatase activity. When injected in vivo to rats, at very small doses, the synthetic osteogenic growth polypeptide increases bone formation and trabecular bone mass.
As in the case of other polypeptide growth regulators, such as growth 33:105!, osteogenic growth polypeptide-binding protein/s (OGPBP) may protect the osteogenic growth polypeptide against proteolytic degradation
C-terminal modified analogues of the osteogenic growth polypeptide, such as do not share the OGP stimulation of cell proliferation and do not react These polypeptide analogues can be used to release OGP from its complex with an OGPBP. If the competitive reaction takes place in a tissue culture medium, previously incubated with cells or a biological fluid having peptidase activity, the released OGP becomes exposed to protelolytic degradation resulting from said peptidase activity. Nevertheless, the possibility existed that short peptides resulting from the proteolytic degradation may retain the OGP activity.
Since the OGP molecule is too large for effective oral administration, it would be of therapeutic importance to find oligopeptides of six or less amino acids residues, that retain the OGP biological activity. such short oligopeptides could be modified into a stable pharmaceutical preparation suitable for oral or other systemic treatment of several pathological conditions, particularly conditions involving loss of bone tissue. In addition, the identification of such oligopeptides would be an essential step towards the definition of the minimal amino acid sequence that still retains the OGP activity, which may provide the basis for further drug design.
The present invention indeed relates to such native or synthetic osteogenically active oligopeptides.
The following abbreviations are used herein: OGP(s)-osteogenic growth polypeptide(s). OGPBP(s)-osteogenic growth polypeptide binding protein(s). irOGP-immunoreactive OGP. sOGP-synthetic OGP.
SUMMARY OF THE INVENTION
The invention relates to biochemically pure oligopeptides having stimulatory activity on osteoblastic and/or fibroblastic cells having a molecular weight between 200and 2,000.
Preferred oligopeptides according to the invention comprise the amino acid sequence: Tyr-Gly-Phe-His-Gly (SEQ ID NO:2) or the amino acid sequence Gly-Phe-Gly-Gly.(SEQ ID NO:3) Particularly preferred are oligopeptides wherein the five C-terminal amino acid residues are the five or four amino acid residues of said amino acid sequences.
The invention also relates to a method of isolating a biochemically pure oligopeptide having stimulatory activity on osteoblastic or fibroblastic cells from a biological sample comprising the steps of: (a) discarding from said biological sample peptides having a molecular weight lower than 3000;(b)
REFERENCES:
patent: 4434094 (1984-02-01), Seyedin et al.
patent: 4455256 (1984-06-01), Urist
Kharchenko, E. P.; Bagrov, A. Historphin--new opiate peptide from histone AU. Dokl. Akad. Nauk SSSR 289:1009-1012, 1986.
Viscontini et al. Pterin Chemistry . . . Helv. Chim Acta, 53(2), 377-383, 1970.
Bab et al (192): EMBO J. vol. 11, No. 5, pp. 1867-1873 Histone H4-related osteogenic growth etc.
Greenberg et al (1993) Biochim. Biophys Act. vol. 1178, No. 3 pp. 273-280 Mitogenic action of osteogenic etc.
Urist et al (1987) Meth. Enzymol. vol. 146 pp. 294-312 Preparation and Bioassay of Bone Morphogenetic etc.
Chemical Abstracts vol. 74, No. 1 Jan. 1971 Sautiere et al.
Chemical Abstracts vol. 76, No. 7 Feb. 1972 Sautiere et al.
Bab Itai
Chorev Michael
Greenberg Zvi
Mansur Nura
Muhlrad Andras
Borin Michael
Tsang Cecilia J.
Yissum Research Development Company of the Hebrew University of
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