Peptide and osteogenetic accelerator

Details Peptide and osteogenetic accelerator Peptide and osteogenetic accelerator

1999-11-12

2003-09-09

Low, Christopher S. F. (Department: 1853)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S326000, C530S334000, C530S344000, C424S422000, C424S423000, C424S426000, C523S115000

Reexamination Certificate

active

06617307

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel peptide having osteogenetic activity and an osteogenetic accelerator containing the same as an active ingredient.
The peptide of the present invention, which has the osteogenetic activity, is useful for treatment of fractures, as a filler in deficient sites of bone, for inhibition of decrease in bone substance related to osteoporosis and periodontic diseases, for prevention of fractures associated with osteoporosis and rheumatoid arthritis and the like.
2. Description of Related Art
Bone morphogenetic protein (BMP) is a member of transforming growth factor (TGF) &bgr; family (Wozney, J. M. et al, Science, 242, 1528 (1988)), and its active form exists as a homodimer having a molecular weight of about 18kD. BMP has the function of acting on undifferentiated mesenchymal cells, inducing differentiation to chondroblasts and osteoblasts and effecting chondrogenesis and osteogenesis (Wang, E. A. et al. Proc. Natl. Acad. Sci. USA, 87, 2220 (1990)).
For this reason, BMP is expected to be effective in treatment of fractures, inhibition of decrease in the bone substance related to osteoporosis and periodontic diseases, in prevention of fractures associated with osteoporosis and rheumatoid arthritis and the like (for example, see Japanese Unexamined Patent Publications Nos.
HEI 6(1994)-298800 and HEI 10(1998)-70989).
Also, there are known a number of inventions relating to implants and compositions in which BMP is combined with a variety of matrices (for example, see Japanese Unexamined Patent Publications Nos. HEI 6(1994)-296677, HEI7(1995)-246235, HEI 7(1995)-116240, HEI 7(1995)-88174 and HEI 10(1998)-151188).
However, the above-described BMP, when it is administered in vivo, disappears from blood within a few minutes and loses its effect. If administered in a large amount for compensating that, BMP might possibly cause various adverse effects, including toxic effects on livers and kidneys. Further, BMP has an immunogenicity because of its large molecular weight, and might possibly cause anaphylactic shock when administered repeatedly. furthermore, where BMP is impregnated in matrices of decalcificated bone or collagen for use, osteogenetic activity is expressed, but there may be another problem of antigenicity or infection attributed to the matrices.
SUMMARY OF THE INVENTION
Under these circumstances, an object of the present invention is to provide a peptide having an osteogenetic activity in which peptide the above-mentioned problems are alleviated, and an osteogenetic accelerator containing the peptide.
According to the present invention, the above-mentioned object is achieved by a peptide having any one of the sequences SEQ ID NO.1 to SEQ ID NO.8.
Also the object of the present invention is achieved by an osteogenetic accelerator containing the above-mentioned peptide.
These and other objects of the present application will become more readily apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The peptides of the present invention are not necessarily required to have exactly the same amino acid sequence as represented by any one of SEQ ID NO.1 to SEQ ID NO.8, provided that they have the osteogenetic activity. In other words, so long as the peptides have the osteogenetic activity, one to several amino acids in the sequences may optionally be deleted or substituted or one to several amino acids may optionally be added to the sequences, by a usual technique in genetic engineering or in peptide synthesis. The optionally deleted, substituted or added amino acids may be selected as appropriate depending on the kind of amino acids, a site and the like.
In the present invention, to “have the osteogenetic activity” may be construed as activity of accelerating the activation of alkaline phosphatase in osteoblasts (Yamaguchi,A., Molecular Medicine, Vol.30, No.10, 1232(1993)) so as to form neogenetic bone or induce growth of existing bone.
In the present specification, amino acid residues are represented by abbreviatory symbols as follows:
Ala: L-alanine residue
Asn: L-asparagine residue
Cys: L-cysteine residue
Gin: L-glutamine residue
Glu: L-glutamic acid residue
Ile: L-isoleucine residue
Leu: L-leucine residue
Lys: L-lysine residue
Pro: L-proline residue
Ser: L-serine residue
Thr: L-threonine residue
Val: L-valine residue
Glx: L-L-glutamine residue or L-glutamic acid residue
Xaa: amino acid defined in each sequence
Also in the present specification, the amino acid sequence of a peptide is written according to the conventional notation, with an amino group at the N-terminal appearing on the left hand of the sequence and carboxyl group at the C-terminal appearing on the right hand thereof.
The amino acid sequences represented by SEQ ID NO.1 to SEQ ID NO.8 may also be represented by the formula:
—Y1-Asn-Y2-Y3-Y4-Pro-Lys-Y5-Cys-Cys-Y6-Pro-Thr-Y7-Le u-Y8-Ala-Y9—,
wherein Y1 is a peptide residue or an amino acid residue selected from the group consisting of Asn-Ser-Val and Ile, Y2 is an amino acid residue or a peptide residue selected from the group consisting of Ser and Pro-Glu, Y3 is an amino acid residue selected from the group consisting of Lys, Ser and Thr, Y4 is an amino acid residue selected from the group consisting of Ile and Val, Y5 is an amino acid residue selected from the group consisting of Ala and Pro, Y6 is an amino acid residue selected from the group consisting of Ala and Val, Y7 is an amino acid residue selected from the group consisting of Glu and Gln, Y8 is an amino acid residue selected from the group consisting of Ser and Asn, Y9 is an amino acid residue or a peptide residue selected from the group consisting of Ile and Ile-Ser.
The peptides of the present invention may be produced by a method usually used for synthesizing peptides, for example, by a solid phase synthesis method or by a liquid phase synthesis method. The solid phase synthesis method is simpler in operation (for example, see “Sequel to Biochemical Experiments 2, Chemistry about Protein (the second volume)” p.p.641-694 edited by the Biochemical Society in Japan published on May 20, 1987 by Tokyo Kagaku Dojin, Japan and “Solid Phase Peptide Synthesis—A Practical Method” p.p.152-154by Atherton, E. et al. published in 1989 by IRL Press, Oxford). The solid phase synthesis can be carried out usually by protecting amino groups with appropriate protecting groups, for example, either Boc (tert-butoxycarbonyl) or Fmoc (9-fluorenylmethyloxycarbonyl), or a combination thereof.
For producing the peptide of the present invention, for example, 1) an amino acid corresponding to the C-terminal of the peptide to be produced is bonded to a solid phase material insoluble to a reaction solvent via an &agr;-COOH group of the amino acid; 2) subsequently, in the direction to the N-terminal of the peptide, a corresponding amino acid or peptide fragment is bonded by condensation to the amino acid of 1) after protecting other functional groups such as an &agr;-amino group of the corresponding amino acid or peptide fragment other than an &agr;-COOH group; 3) a protecting group of an amino group forming a peptide bond such as an &agr;-amino group is removed from the bonded amino acid or peptide fragment; these steps are repeated to elongate a peptide chain in order to form a peptide chain corresponding to the desired peptide.
The thus produced peptide chain is detached from the solid phase material and protecting groups are removed from protected functional groups. Subsequently the peptide chain is purified, thereby to obtain the desired peptide.
Here, as the solid phase material, styrene-divinyl benzene copolymers, Merrifield resins, chloromethyl resins,

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