Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1997-10-14
1999-11-09
Wax, Robert A.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 13, 514 14, 514 17, 530324, 530326, 530327, 530329, A61K 3800, A61K 3804
Patent
active
059814861
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a peptide capable of inhibiting phosphorylation of I.kappa.B.alpha., and more particularly, to a peptide useful as an antiphlogistic or immunosuppressant.
BACKGROUND ART
A region referred to as .kappa.B and usually composed of 10 nucleotides was clearly shown to promote gene transcription activity as a part of an enhancer by analysis of the protein-binding region in the enhancer region of human immunodeficiency virus (HIV) and antibody .kappa. light chain. When the transcription regulating protein, nuclear factor .kappa.B (NF.kappa.B) binds to this region, transcription of gene downstream from the .kappa.B region is promoted (Gilmore, T. & Morin, P. J.: Trends in Genetics (1993) 9, 427-432).
According to a study using a pre-B cell line, 70Z/3 cells, and Hela cells, it is known that these cells contain in their cytoplasm NF.kappa.B that does not have any DNA binding activity, and that by phorbol ester stimulation, the DNA binding activity is derepressed causing NF.kappa.B to translocate into the nucleus (Baeuerle, P. A. & Baltimore, D.: Cell (1988) 53, 211-217).
NF.kappa.B is a heterodimeric or homodimeric transcription factor comprising two subunits (p50, p65), and is induced by various stimuli. It is currently estimated to be involved in the transcription activity of more than 20 genes (Baeuerle, P. A.: Biochim. Biophys. Acta (1991) 1072; 63-80).
NF.kappa.B is also located upstream from the cytokine genes of Interleukin-8, Interleukin-1.beta., tumor necrosis factor (TNF)-.alpha., Interleukin-6 and Interleukin-2 as well as cyclooxygenase-2 (Kujubu, D. A. et al., J. Biol. Chem. (1991) 266, 12866-12872) or 5-lipoxygenase (Hoshiko, S. et al., Proc. Natl. Acad. Sci. U.S.A. (1990) 87, 9073-9077; Chopra, A. et al., Biochem. Biophys. Res. Commun. (1992) 185, 489-495), which are enzymes involved in the biosynthesis of metabolites of the arachidonic acid cascade, mediators of inflammations, and the genes of adhesion factors such as ELAM-1 (endothelial leukocyte adhesion molecule-1) (Hooft van Huijsduijnen, R. et al., J. Biol. Chem. (1992) 267, 22385-22391) and VCAM-1 (Vascular Cell Adhesion Molecule-1) (Iademarco, M. F. et al., J. Biol. Chem. (1992) 267, 16323-16329). NF.kappa.B is considered to be involved in the control of the transcription of these genes.
The action of steroids, which are currently used as antiinflammatory agents (Mukaida, N. et al., J. Biol. Chem. (1994) 269, 13289-13295) and the powerful immunosuppressant, FK-506 (Okamoto, S.-i. et al., J. Biol. Chem. (1994) 269, 8582-8589) is suggested to at least involve an inhibition of the activation of NF.kappa.B. In the cytoplasm, NF.kappa.B binds with protein I.kappa.B.alpha., which inhibits the function of NF.kappa.B, resulting in inhibition of its activation (Inoue, J-I. et al., Proc. Natl. Acad. Sci. USA (1992) 89, 4333-4337; Hatada, E. et al., EMBO (1993) 12, 2781-2788).
Zabel, U. et al. reported to have isolated I.kappa.B.alpha. as a 37 kDa homogeneous protein from human placenta (Cell (1990) 61, 255-265). This was followed by the isolation of the cDNA of human I.kappa.B.alpha. (Sporn, S. A. et al., J. Immunol. (1990) 144, 4434-4441; Haskill, S. et al., Cell (1991) 65, 1281-1289, see WO 92-20795).
I.kappa.B.alpha. not only inhibits the binding of NF.kappa.B to DNA, but also inhibits the translocation of NF.kappa.B into the nucleus (Baeuerle, P. A. & Baltimore, B. Science (1988) 242, 540-546). I.kappa.B.alpha. has been clearly shown to be phosphorylated in response to various stimuli such as TNF.alpha. and so forth.
NF.kappa.B translocates into the nucleus and binds to the protein-binding site on DNA as a result of phosphorylation or degradation of I.kappa.B.alpha. in this manner or by phosphorylation of the proteins comprising NF.kappa.B, followed by activation of the transcription of genes located downstream (Baeuerle, P. A.: Biochim. Biophys. Acta (1991) 1072, 63-80). Although the above-mentioned mechanism is known to occur at the time of activation of NF.kappa.B, the enzyme group that phosphor
REFERENCES:
Barroga et al., "Constitutive phosphorylation of IkB.alpha.by casein kinase II". Proc. Natl. Acad Sci. USA92: 7637-7641 (1995).
Kuno et al., Identification of an Ikb.alpha.-associated Protein Kinase in a Human Monocytic Cell Line and Determination of its Phosphorylation Sites on IkB-.sub..alpha..degree. The Journal of Biological Chemistry270: 27914-27919 (1995).
"Proceedings of the Japanese Society for Immunology" vol.25 p. 156 (1995) English Translation.
Ishikawa Yuji
Kuno Kouji
Matsushima Kouji
Chugai Seiyaku Kabushiki Kaisha
Slobodyansky Elizabeth
Wax Robert A.
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