Tryptase inhibitor

Details Tryptase inhibitor Tryptase inhibitor

1996-01-25

1999-10-26

Jacobson, Dian C.

Chemistry: molecular biology and microbiology

Vector, per se

435 692, 435212, 514 12, 530324, 536 235, C07K 14815, C12N 1511, A61K 3858

Patent

active

059726989

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to novel inhibitors of human tryptase to their isolation from leeches, to nucleotide sequences encoding the novel inhibitor molecules or fragments thereof, to vectors containing the coding sequence thereof, to host cells transformed with such vectors, to the recombinant production of the inhibitors, to pharmaceutical compositions containing the novel inhibitor molecules, and to their use in diagnosis and therapy.
Tryptase is a tetrameric member of the family of trypsin-like serine proteinases. Tryptase is expressed virtually exclusively by mast cells [Castells Irani, 1987] and stored in large amounts in their secretory granules, constituting .about.23% of the total cellular protein [Schwartz Lewis Austen, 1981]. Following activation of mast cells, tryptase is rapidly released into the extracellular space together with other preformed mediators (e.g. histamine, chymase, and proteoglycans) [Schwartz Lewis Seldin, 1981; Caughey Lazarus, 1988]. Elevated levels have been found [Schwartz Metcalfe, 1987; Schwartz Yunginger, 1989], and during the systemic response after aspirin challenge of patients with aspirin-sensitive asthma [Bosso Schwartz, 1991], 1991; Bousquet Chanez, 1991; Wenzel Fowler, 1988], interstitial lung diseases [Walls Bennett, 1991], and after antigen challenge of allergic patients [Castells, 1988; Butrus, 1990], with atopic and allergic skin disease [Shalit Schwartz, 1990; Atkins Schwartz, 1990], seasonal allergic rhinitis [Juliusson Holmberg, 1991], Eley, 1989, J Period Res; Eley Cox, 1992, J Dent], and 1989].
In vitro studies have provided considerable evidence that tryptase is directly involved in the pathogenesis of mast cell related disorders. For example, tryptase has been suggested as a pathogenetic mediator of asthma as it increases the contractility of airway smooth muscle [Sekizawa, 1989] and inactivates vasoactive intestinal peptide, thereby destroying its potent bronchodilatatory action [Tam Caughey, 1990; Tam Franconi, 1990; Franconi, 1989]. In addition, tryptase has been shown to be a potent mitogen for fibroblasts, suggesting its involvement in the pulmonary fibrosis in asthma and interstitial lung diseases [Ruoss Hartmann, 1991; Hartmann Ruoss, 1992]. Tryptase has also been implicated in the pathogenesis of arthritis and periodontal disease, as it activates prostromelysin (=MMP-3) which in turn activates collagenase, thereby initiating the destruction of cartilage and periodontal connective tissue, respectively [Gruber Marchese, 1989; Gruber Schwartz, 1990; Cox Eley, 1989, J Period Res; Eley Cox, 1992, J Dent]. Tryptase may also promote blood clotting disorders by inactivating the procoagulant function of high molecular weight kininogen [Maier Spragg, 1983] and by cleaving fibrinogen [Schwartz Bradford Littman, 1985].
Human tryptase is virtually unique among the serine proteinases as it is fully catalytically active in plasma and in the extracellular space [Schwartz Bradford, 1986; Goldstein Leong, 1992]. Tryptase is not inhibited by the naturally occurring antiproteinases regulating the activity of other trypsin-like serine proteinases such as mucus-proteinase inhibitor (=antileukoprotease or HUSI-I), antithrombin III, alpha.sub.1 -proteinase inhibitor, alpha.sub.2 -macroglobulin, or C.sub.1 -esterase inhibitor [Alter Kramps, 1990; Smith Hougland, 1984; Schwartz Bradford, 1986; Harvima Schechter, 1988; Cromlish Seidah, 19873]. Furthermore, although tryptase has been known for over 10 years, inhibitors derived from non-human species or produced by peptide synthesis or recombinant technologies have not yet been described. Thus, tryptase is not affected by hirudin [Alter Kramps, 1990], aprotinin, ovomucoid inhibitor, soybean and lima bean trypsin inhibitor [Butterfield Weiler, 1990; Cromlish Seidah, 1987; Harvima Schechter, 1988], ecotin [Chung Ives, 1983], and the recombinant Kunitz-domain of the Alzheimer beta-amyloid precursor-protein [Sinha Dovey, 1990].
Although tryptase is inhibited by the general inhibitors of trypsin-like proteinases such as di

REFERENCES:
patent: 4595674 (1986-06-01), Tschesche et al.
patent: 4666829 (1987-05-01), Glenner et al.
patent: 4912206 (1990-03-01), Goldgaber et al.

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