Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 24 amino acid residues in defined sequence
Patent
1993-11-10
1996-12-03
Davenport, Avis M.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
24 amino acid residues in defined sequence
530326, 530327, 530328, 530329, A61K 3800, C07K 700, C07K 500, C07K 1700
Patent
active
055809561
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 continuation-in-part of PCT/JP93/00299 filed Mar. 11, 1993 and published as WO93/18062 Sep. 16, 1993.
TECHNICAL FIELD
The present invention relates to novel peptides which have phospholipase C (hereinafter referred to as PLC)-inhibiting activity.
PRIOR ART
The isolation and purification, from various tissues, of PLC, for example, phospholipid inositol PLC (hereinafter referred to as PI-PLC), has been carried out in order to understand the mechanism of intracellular signal transduction pathway, and heretofore, the existence of 9 different isozymes thereof classified into 4 types, .alpha., .beta., .gamma. and .delta. has been found. Two types are known as .gamma. type, .gamma..sub.1 and .gamma..sub.2 (S. G. Rhee et al., Science, 244, 546-550, 1989; Y. Homma et al., Biochemical Journal, 269, 13-18, 1990), and both have been shown to play an important role in the signal transduction of growth factor. The structural characteristics of .beta., .gamma. and .delta. types is that oncogene src Homology regions, SH2 and SH3 (SH2/SH3) regions are located between I and II regions commonly found in .beta., .gamma. and .delta., and the SH2 region of the .gamma. type is essential for interaction with receptor-type tyrosine kinase (D. Anderson et al., Science, 250, 979-982, 1990). The function of the SH3 region of the .gamma. type is not clear, but it has been suggested that it is important for interaction with the cytoskeletal system. Also, with the discovery of the oncogene crk which has SH2 and SH3 (SH2/SH3) regions but no kinase region, attention has centered on the possibility that disturbances in the regulation via the SH2 and SH3 (SH2/SH3) regions of the .gamma. type (abnormalities in PI-PLC activation) and cell proliferation abnormalities may lead to canceration. Furthermore, there has been reports showing that elevated PLC activity is related with pathology, among them a report that PLC contributes to the thrombin-induced platelet activation system (Journal of Biological Chemistry, 261, 16838-16847, 1986), a report that PLC activity contributes to the release of histamine (Journal of Cell Biology, 105, 2745-2750, 1987), a report that PLC contributes to the signal transduction pathway of the receptor for N-formyl-methionyl-leucyl-phenylalanine, which is known as a substance which provokes inflammation by means of granulocytes and polymorphonuclear leukocytes (PMNs) (Science, 232, 97-100, 1986), a report that the platelet-derived growth factor (PDGF) .beta.-chain protein is expressed in large amounts in arteriosclerotic lesions (Science, 248, 1009, 1990), a report that PLC-.gamma..sub.2 is present as a constituent of the signal transduction for PDGF-dependent proliferation of vascular smooth muscle cells, and is prominently involved in the proliferation of smooth muscle cells (Biochemical and Biophysical Research Communications, 156, 846-854, 1988; Biochemical Journal, 290, 649-653, 1993) and a report that PLC is stimulated in conditions of Alzheimer's disease (American Journal of Pathology, 139, 737-742, 1991). It is expected that the pathological conditions may be improved by inhibiting PLC activity, and thus it has been sought to provide an inhibiting agent against PLC activity. As peptides which have PLC inhibiting activity, the peptides defined in Sequence Listing by SEQ ID: Nos. 1-5, 7 and 8 have been published in the Journal of Biological Chemistry, Vol. 267, pp. 21844-21849, 1992, subsequent to the application (Japanese Unexamined Unpublished Patent No. 52394/92; Date of application: Mar. 11, 1992) on which the convention priority of the present application is founded.
DISCLOSURE OF THE INVENTION
According to the present invention, provided is a peptide which has phospholipase C-inhibiting activity and has the amino acid sequence as defined in Sequence Listing by SEQ ID: No. 1; or a modified peptide in which one or more of the amino acid residues of the above-mentioned peptide are deleted, in which one or more amino acid residues are added to the above mentioned peptide, an
REFERENCES:
Emori et al., J. Biol. Chem., vol. 264, No. 36, pp. 21885-21890, Dec. 1989.
Ohta et al., FEBS Lett, vol. 242, No. 1, pp. 31-35, Dec. 1988.
Homma et al., J. Biol. Chem., vol. 267, No. 30, pp. 21844-21849, Oct., 1992.
Homma, et al., Biochemical and Biophysical Research Communications, 182(3): 1402-1407 (1992).
S. G. Rhee, et al., Science 244, 546-550, 1989.
Y. Homma, et al., Biochemical Journal, 269, 13-18, 1990.
D. Anderson, et al., Science 250, 979-982, 1990.
Journal of Biological Chemistry, 261, 16838-16847, 1986.
Journal of Cell Biology, 105, 2745-2750, 1987.
Science, 232, 97-100, 1986.
Science, 248, 1009, 1990.
Biochemical and Biophysical Research Communications, 156, 846-854, 1988.
Biochemical Journal, 290, 649-653, 1993.
American Journal of Pathology, 139, 737-742, 1991.
The Journal of Antibiotics, vol. 45, No. 8, pp. 1365-1366.
Honma Yoshimi
Ishikawa Genkichi
Saito Hiromitsu
Yamasaki Motoo
Davenport Avis M.
Kyowa Hakko Kogyo Co. Ltd.
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