Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1996-09-25
1998-08-18
Degen, Nancy
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
435 71, 435 76, 435 771, 435 772, 530317, 530412, A61K 3812, C07K 512, C07K 122, G01N 3353
Patent
active
057958653
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel classes of proteins and protein analogues which bind to and inhibit human plasma kallikrein.
2. Description of the Background Art
Kallikreins are serine proteases found in both tissues and plasma. Plasma kallikrein is involved in contact-activated (intrinsic pathway) coagulation, fibrinolysis, hypotension, and inflammation. (See BHOO92). These effects of kallikrein are mediated through the activities of three distinct physiological substrates: i) Factor XII (coagulation), ii) Pro-urokinase/plasminogen (fibrinolysis), and iii) Kininogens (hypotension and inflammation).
Kallikrein cleavage of kininogens results in the production of kinins, small highly potent bioactive peptides. The kinins act through cell surface receptors present on a variety of cell types. Intracellular heterotrimeric G-proteins link the kinin receptors to second messenger pathways including nitric oxide, adenyl cyclase, phospholipase A.sub.2, and phospholipase C. Among the significant physiological activities of kinins are: (i) increased vascular permeability; (ii) vasodilation; (iii) bronchospasm; and (iv) pain induction. Thus, kinins mediate the life-threatening vascular shock and edema associated with bacteremia (sepsis) or trauma, the edema and airway hyperreactivity of asthma, and both inflammatory and neurogenic pain associated with tissue injury. The consequences of inappropriate plasma kallikrein activity and resultant kinin production are dramatically illustrated in patients with hereditary angioedema (HA). HA is due to a genetic deficiency of C1-inhibitor, the principal endogenous inhibitor of plasma kallikrein. Symptoms of HA include edema of the skin, subcutaneous tissues and gastrointestinal tract, and abdominal pain and vomiting. Nearly one-third of HA patients die by suffocation due to edema of the larynx and upper respiratory tract. Kallikrein is secreted as a zymogen (prekallikrein) that circulates as an inactive molecule until activated by a proteolytic event that frees the +NH.sub.3 -IVGGTNSS . . . sequence of kallikrein (SEQ ID NO. 1). Human Plasma Prekallikrein is found in Genebank entry
Mature plasma Kallikrein contains 619 amino acids. Hydrolysis of the Arg.sub.371 -Ile.sub.372 peptide bond yields a two-chain proteinase joined by a disulfide bond. The amino-terminal light chain (248 residues) carries the catalytic site.
The main inhibitor of plasma kallikrein (pKA) in vivo is the C1 inhibitor; see SCHM87, pp.27-28. C1 is a serpin and forms an essentially irreversible complex with pKA. Although bovine pancreatic trypsin inhibitor (BPTI) was first said to be a strong pKA inhibitor with K.sub.i =320 pM (AUER88), BERN93 indicates that its K.sub.i for pKA is 30 nM (i.e., 30,000 pM). The G36S mutant had a K.sub.i of over 500 nM. Thus, there is a need for a safe kallikrein inhibitor. The essential attributes of such an agent are: immunogenicity and organ/tissue toxicity.
The candidate target kallikreins to be inhibited are chymotrypsin-homologous serine proteases.
Excessive Bleeding
fibrinolytic activity, or a combination of the two. In most diatheses one must controll the activity of plasmin. However, plasma kallikrein (pKA) is an activator of plasminogen and a potent, selective pKA inhibitor may avert plasminogen activation. The clinically beneficial effect of BPTI in reducing blood loss is thought to result from its inhibition of plasmin (K.sub.D .about.0.3 nM) or of plasma kallikrein (K.sub.D .about.100 nM) or both enzymes. It has been found, however, that BPTI is sufficiently antigenic that second uses require skin testing. Furthermore, the doses of BPTI required to control bleeding are quite high and the mechanism of action is not clear. Some say that BPTI acts on plasmin while others say that it acts by inhibiting plasma kallikrein. FRAE89 reports that doses of about 840 mg of BPTI to 80 open-heart surgery patients reduced blood loss by almost half and the mean amount transfused was decreased by 74%. Miles Inc. has recently in
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M
Ladner Robert Charles
Markland Willaim
Cooper Iver P.
Degen Nancy
Dyax Corp.
Yankwich Leon R.
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