Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Peptides with at least one nonpeptide bond other than a...
Patent
1996-11-08
1997-10-14
Degen, Nancy
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Peptides with at least one nonpeptide bond other than a...
530328, 530327, 530326, 530325, A61K 3800, C07K 700, C07K 500, C07K 1700
Patent
active
056774206
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 continuation of PCT/JP96/00556, filed Mar. 7, 1996, and published as WO96/28466 on Sep. 19, 1996.
TECHNICAL FIELD
The present invention relates to novel peptides which inhibit phospholipase C (hereinafter referred to as PLC) activity.
PRIOR ART
PLC, e.g., phosphatidyl inositol PLC (hereinafter referred to as PI-PLC), has been isolated and purified from various tissues in order to elucidate the mechanism of intracellular signal transduction, and the existence of nine isozymes classified into 4 types, .alpha., .beta., .gamma. and .delta. has been found so far. Type .gamma. is known to occur in two kinds, .gamma..sub.1 and .gamma..sub.2 (S.G. Rhee et al., Science, 244, 546-550, 1989; Y. Honma et al., Biochem. J., 269, 13-18, 1990), both of which have been discovered to play an important role in the signal transduction of growth factors. The structural characteristic of types .beta., .gamma. and .delta. is that they contain oncogene src-associated regions, SH2 and SH3 (SH2/SH3) regions between I and II regions common to .beta., .gamma. and .delta.. The SH2 region of type .gamma. is essential for the interaction with receptor-type tyrosine kinase (D. Anderson et al., Science, 250, 979-982, 1990). The function of the SH3 region of type .gamma. is not clear, but it is supposed to be important for the interaction with the cytoskeletal system. Recently the oncogene crk which has SH2 and SH3 (SH2/SH3) regions but no kinase region was found and this has highlighted the possibility that the regulation disorders (abnormality in PI-PLC activity) and abnormal cell proliferation as mediated by the SH2 and SH3 (SH2/SH3) regions of type .gamma. may induce cancerous alteration. Further, there are reports which disclose that elevated PLC activity is related with pathology; for example, a report that PLC is associated with the thrombin-induced platelet activation system (J. Biol. Chem., 261, 16838-16847, 1986), a report that PLC activity is associated with histamine release (J. Cell Biol., 105, 2745-2750, 1987), a report that PLC is associated with the signal transduction pathway of the receptor for N-formylmethionyl-leucyl-phenylalanine, which is known as a substance to induce inflammation via granulocytes and polymorphonuclear leukocytes (PMN) (Science, 232, 97-100, 1986), a report that the .beta.-chain of a platelet-derived growth factor (PDGF) is expressed in large amounts in arteriosclerotic lesions (Science, 248, 1009, 1990), reports that PLC-.gamma..sub.2 exists as a constituent of the signal transduction system for the proliferation of PDGF-dependent vascular smooth muscle cells, and is closely associated with the proliferation of smooth muscle cells (Biochem. Biophys. Res. Commun., 156, 846-854, 1988, Biochem. J., 290, 649-653, 1993), and a report that PLC is increased in Alzheimer's disease (Am. J. Pathol., 139, 737-742, 1991). It is expected that these diseases can be alleviated by inhibiting PLC activity and there is a need for agents which inhibit PLC activity.
As PLC-inhibiting peptides, the following peptides are disclosed in J. Biol. Chem., 267, 21844-21849 (1992): Ser-Leu-Val-Glu-Leu-Val-Ser-Tyr-Tyr-Glu-Lys-His-Ala-Leu-Tyr-Arg-Lys-Met-Ar g-Leu-Arg-Tyr-Pro-Val, Ser-Tyr-Tyr-Glu-Lys-His-Ala-Leu-Tyr-Arg-Lys-Met, Glu-Lys-His-Ala-Leu-Tyr-Arg-Lys-Met, Glu-Lys-His-Ala-Leu-Tyr-Arg-Lys-Met-Arg-Leu-Arg-Tyr-Pro-Val, Leu-Tyr-Arg-Lys-Met-Arg-Leu-Arg-Tyr-Pro-Val, Tyr-Arg-Lys-Met-Arg-Leu-Arg-Tyr, and Arg-Lys-Met-Arg-Leu-Arg.
DISCLOSURE OF THE INVENTION
The present invention provides phospholipase C-inhibiting peptides represented by formula (I): ##STR2## wherein n represents 0 or 1; each J.sup.1 and J.sup.2 is a hydrogen atom, or J.sup.1 and J.sup.2 are combined together to form a single bond; W represents a hydrogen atom, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted aroyl group or coumaryl group; X represents a single bond, -Leu-, or -Ser-Leu-Val-Glu-Leu-Val-Ser-Tyr-Tyr-Glu-Lys-His-Ala-Leu- (wherein at least one amino acid residue may be deleted, inserted or
REFERENCES:
patent: 5580956 (1996-12-01), Saito et al.
J. Biological Chemistry, vol. 267, No. 30 (Oct. 1992) pp. 21844-21849.
J. Biological Chemistry, vol. 264, No. 36 (Dec. 1989) pp. 21885-21890.
Honma Yoshimi
Ishikawa Genkichi
Yamasaki Motoo
Degen Nancy
Kyowa Hakko Kogyo Co. Ltd.
Latimer Matthew
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