Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1994-02-09
1995-12-05
Russel, Jeffrey E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 21, 530380, A61K 3817, C07K 1447
Patent
active
054729459
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to the modulation of blood pressure and the management of hypertension by manipulating the extent and location of bradykinin availability in the circulatory system. The invention also relates to the inhibition of thrombin-induced platelet and endothelial cell activation.
BACKGROUND OF THE INVENTION
The kininogens are single-chain glycoproteins which are present in human blood plasma and tissues in two forms: high molecular weight kininogen (120 kDa) and low molecular weight kininogen (64 kDa). A single gene controls the synthesis of both kininogens (Takagaki et al., J. Biol. Chem. 266, 6786 (1985)). The difference between the high molecular weight form and the low molecular weight form is the addition of a unique 56 kDa light chain on high molecular weight kininogen by an alternative mRNA splicing of the single kininogen gene (Kitamura et al., J. Biol. Chem. 260, 8610 (1985); Kakizuka et al., J. Biol. Chem. 265, 10102 (1990)). The presence of the 56 kDa light chain on high molecular weight kininogen gives this form of kininogen unique antigenic and functional properties. The plasma concentration of high molecular weight kininogen is 0.67 micromolar, while the plasma concentration of low molecular weight kininogen is 2.4 micromolar.
There are numerous functions for the plasma kininogens which follow from their structure. The first function of both kininogens is that they serve as the parent proteins for the nonapeptide bradykinin, and for the decapeptide lys-bradykinin. These kinins are the most potent, naturally-occurring vasodilitory mediators. They have profound effects on endothelium, stimulating their prostaglandin synthetic pathways and stimulating release of plasminogen activators. Bradykinin and its derivatives may be major local modulators of the autocrine regulation of blood pressure. Bradykinin is best liberated from high molecular weight kininogen by plasma kallikrein, activated factor XII, factor XIa and plasmin. Low molecular weight kininogen is a better substrate for tissue kallikreins liberating lysbradykinin. Elastase treatment of low molecular weight kininogen makes it a better substrate for kinin release by plasma kallikrein.
Both low and high molecular weight kininogens have identical amino acid sequences from their N-terminus through 12 amino acids beyond the carboxy-terminus of bradykinin. Their so-called "heavy chains" from the amino-terminus of the protein to the amino-terminal end of bradykinin are identical. These heavy chains have been characterized to have three domains (domains 1-3). Domains 2 and 3 contain the amino acid sequence Gln-Val-Val-Ala-Gly (SEQ ID NO:2). This amino acid sequence is highly conserved in evolution in cysteine protease inhibitors (Ohkubo et al., Biochem. 23, 3891 (1984)). Domain 2 uniquely appears to be a good inhibitor of calpains, which are calcium-dependent tissue cysteine proteases (Schmaier et al, J. Clin. Invest. 77, 1565 (1986)). The kininogens' ability to inhibit calpains may have some function in preventing calpain-induced platelet aggregation after thrombin activation (Schmaier et al., Blood 75, 1273 (1990)). Domain 4 on both high and low molecular weight kininogen comprises bradykinin.
High molecular weight kininogen also functions as a cofactor for the activation of the following plasma zymogens: factor XII, prekallikrein, and factor XI. These three plasma zymogens when activated to enzymes, along with high molecular weight kininogen, comprise the proteins of the contact phase of plasma proteolysis. In addition to being a cofactor for activation of each of these plasma zymogens, high molecular weight kininogen is also a substrate of each of their proteolytic forms. The procofactor activity of high molecular weight kininogen is based upon two areas on its unique 56 kDa light chain: First, high molecular weight kininogen has a region on domain 5 which is rich in the basic amino acids glycine, histidine, and lysine that has the ability to bind to anionic surfaces such as kaolin. Secondly, high mol
REFERENCES:
patent: 3862114 (1975-01-01), Scandrett
patent: 4378346 (1983-03-01), Tankersky
patent: 4638047 (1987-01-01), Szelke et al.
patent: 4908431 (1990-03-01), Colman et al.
patent: 5037957 (1991-08-01), Grubb et al.
Cell, vol. 50, issued 28 Aug. 1987, Reeck et al, "Homology in Proteins and ucleic Acids . . . ", p. 667.
Eur. J. Biochem., vol. 142, issued 1984, Lottspeich et al, "Human Low-Molecular-Mass Kininogen", pp. 227-232.
Jiang et al., The Journal of Biological Chemistry, vol. 267, No. 8, pp. 3712-3717 (Feb. 1992).
Van Iwaarden et al., The Journal of Biological Chemistry, vol. 263, No. 10, pp. 4698-4703 (Apr. 1988).
Kellermann et al., European Journal of Biochemistry 154, 471-478 (1986).
Muller-Esterl, Atemw.-Lungenkrkh., Jahrg. 14, 1. Suppl. 511-522 (1988).
Vogel et al., The Journal of Biological Chemistry, vol. 263, No. 25, pp. 12661-12668 (Sep. 1988).
Salvesen et al., Biochem. J., 234, 429-434 (1986).
Gustafson et al., J. Clin. Invest., 78, 310-318 (Jul. 1986).
Gustafson et al., J. Clin. Invest., 84, 28-35 (Jul. 1989).
Greengard et al., Biochemistry, 23, 6863-6869 (1984).
Meloni et al., The Journal of Biological Chemistry, 266, No. 11, 6786-6794 (1991).
Neely et al., Blood 72: (Suppol.) 304a (1988) Abs.
Gustafson et al., Clinical Research 34, No. 2 459A (1986) (Abs.).
Meloni et al., Circulation 78: (Suppl.) II-545 (1988) (Abs.).
Schmaier et al., J. Biol. Chem. 263, 16327-16333 (1988).
Kuna et al., Blood 76: (Suppl.) 426a (1990) (Abs.).
Jiang Yongping
Schmaier Alvin H.
Russel Jeffrey E.
Temple University- of the Commonwealth System of Higher Educatio
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