Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 24 amino acid residues in defined sequence
Patent
1995-05-05
1998-12-08
Tsang, Cecilia J.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
24 amino acid residues in defined sequence
530327, C07K 900
Patent
active
058470743
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel peptides which inhibit the phopholipase C (hereinafter referred to as "PLC") activity.
BACKGROUND ART
PLC, e.g., inositolphospholipid PLC (hereinafter referred to as "PI-PLC") was separated and purified from various tissues for the purpose of elucidation of intracellular signal transduction pathway and the existence of nine isozymes in four types (.alpha., .beta., .gamma.and .delta.) has been demonstrated. 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. Homma et al., Biochem.J., 269, 13-18 (1990)). Both kinds have been shown to play an important role in signal transduction of growth factors. The structural feature of the .beta., .gamma. and .delta. types is that they contain an oncogene src-associated region, SH2/SH3 region, between I and II regions common to .beta., .gamma. and .delta.. SH2 region in the .gamma. type is essential for the interaction with a receptor-type tyrosine kinase (D. Anderson et al., Science, 250, 979-982 (1990)). Although the function of SH3 region in the .gamma. type has not been clear, it is presumably important for the interaction with cytoskeletons. Recently, the oncogene crk having SH2/SH3 region but not kinase region was found and this has highlighted the possibility that the regulation disorder (abnormal activity of PI-PLC) and abnormal cell proliferation as mediated by SH2/SH3 region may induce tumor. There are many other reports that review the association of increased PLC levels with pathologic conditions:
PLC is associated with the system of platelet activation by thrombin (J. Biol. Chem., 261, 16838-16847 (1986)); PLC activity is associated with histamine release (J. Cell Biol., 105, 2745-2750 (1987)); PLC is associated with the system of signal transduction by a receptor for N-formyl-methionyl-leucyl-phenylalanine which is known to induce inflammation via granulocytes and polymorphonuclear leukocytes (PMN) (Science, 232, 97-100 (1986)); the .beta. chain of a platelet-derived growth factor (PDGF) is expressed in a large amount in arteriosclerotic lesions (Science, 248, 1009 (1990)); PLC-.gamma..sub.2 is present as a component in the signal transduction system for the proliferation of PDGF-dependent vascular smooth muscle cells and hence is closely associated with the smooth muscle cell proliferation system (Biochem. Biophys. Res. Commun., 156, 846-854 (1988); Biochem.J., 290, 649-653 (1993)); and PLC is increased in Alzheimer's disease (Am. J. Pathol., 139, 737-742 (1991)). Hence, it is expected that the aforementioned diseases can be alleviated by inhibiting the PLC activity and there is a need for agents that inhibit the PLC activity.
The following peptides are disclosed in J. Biol. Chem., 267, 21844-21849 (1992) as being capable of inhibiting the PLC activity: -Leu-Arg-Tyr-Pro-Val, Glu-Lys-His-Ala-Leu-Tyr-Arg-Lys-Met,
DISCLOSURE OF THE INVENTION
According to the present invention, phopholipase C-inhibiting peptides which are represented by formula (I) (hereinafter referred to as "Compound(s) (I)") can be provided: ##STR2## wherein J.sup.1 and J.sup.2 are each hydrogen or combined together to form a single bond; W is hydrogen, a substituted or unsubstituted alkanoyl, a substituted or unsubstituted aroyl or coumaryl; X is a single bond, -Leu- or -Ser-Leu-Val-Glu-Leu-Val-Ser-Tyr-Tyr-Glu-Lys-His-Ala-Leu- (at least one of the N-terminal 14 amino acid residues may be deleted); Y is a single bond or -Pro-Val-; and Z is hydroxy or amino.
In the definition of Compounds (I), the substituted or unsubstituted alkanoyl may be exemplified by those having 1-20 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, caprylayl, lauroyl, myristoyl, palmitoyl, and stearoyl. Exemplary substituents include carboxy, alicyclic alkyl, and phenyl. Exemplary alicyclic alkyls include those having 3-8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The substituted or unsubstituted ar
REFERENCES:
patent: 5580956 (1996-12-01), Saito et al.
Rhee et al, Studies of Inositol Phospholipid-Specific Phospholipase C, Science, vol. 244, pp. 546-550, May 1989.
Homma et al, Isolation and Characterization of a .gamma.-Type Phosphoinositide-Specific Phospholipase C(PLC-.gamma..sub.2, ), Biochem. J., vol. 269, pp. 13-18, 1990.
Anderson et al, Binding of SH2 Domains of Phospholipase C.gamma.1, GAP, and SRC to Activated Growth Factor Receptors, Science, vol. 250, pp. 979-982, Nov. 1990.
Brass et al, Regulation of the Phosphoinositide Hydrolysis Pathway in Thrombin-Stimulated Platelets by a Pertussis Toxin-Sensitive Guanine Nucleotide-Binding Protein, The Journal of Biological Chemistry, vol. 261, No. 36, pp. 16838-16847, Dec. 1986.
Cockcroft et al, Two G-Proteins Act in Series to Control Stimulus-Secretion Coupling in Mast Cells: Use of Neomycin to Distinguish Between G-Proteins Controlling Polyphosphoinositide Phosphodiesterase and Exocytosis, The Journal of Cell Biology, vol. 105, No. 6, Pt.1) pp. 2745-2750, Dec. 1987.
Smith et al, Receptor-Coupled Activation of Phosphoinositide-Specific Phospholipase C by an N Protein, Science, vol. 232, pp. 97-100, Apr. 1986.
Ross et al, Localization of PDGF-B Protein in Macrophages in All Phases of Atherogensis, Science, vol. 248, pp. 1009-1012, May 1990.
Kawahara et al, Platelet-Derived Growth Factor (PDGF)-Induced Phospholipase C-Mediated Hydrolysis of Phosphoinositides in Vascular Smooth Muscle Cells--Different Sensitivity of PDGF-and Angiotensin II-Induced Phospholipase C Reactions to Protein Kinase C-Activating Phorbol Esters, Biochemical and Biophysical Research Communications, vol. 156, No. 2, pp. 846-854, Oct. 31, 1988.
Homma, et al, Evidence for Involvement of Phospholipase C-.gamma.2 in Signal Transduction of Platelet-Derived Growth Factor in Vascular Smooth-Muscle Cells, Biochem. J., vol. 290, pp. 649-653, 1993.
Shimohama et al, Aberrant Accumulation of Phospholipase C-Delta in Alzheimer Brains, American Journal of Pathology, vol. 139, No. 4, pp. 737-742, Oct. 1991.
Homma et al, Inhibitory Effect of SRC Homology (SH) 2/SH3 Fragments of Phospholipase C-.gamma. on the Catalytic Activity of Phospholipase C Isoforms, The Journal of Biological Chemistry, vol. 267, No. 30, pp. 21844-21849, Oct. 25, 1992.
Homma et al, Suppression of Membrane Phospholipase C Activity by Synthetic Autoinhibitor Peptides, Methods: A Comparison to Methods in Enzymology 5, 229-232 (1993).
Hanby, "Conformational Restrictions on Peptides" Life Sciences, v.31, pp. 189-199 (1982).
Konig, "Peptide Useful as Phospholipase Inhibitor" WPIDS Abstract
Honma Yoshimi
Ishikawa Genkichi
Yamasaki Motoo
Delaney Patrick R.
Kyowa Hakko Kogyo Co. Ltd.
Tsang Cecilia J.
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