Protease inhibitors derived from guamerin

Details Protease inhibitors derived from guamerin Protease inhibitors derived from guamerin

1998-05-07

2001-02-06

Tate, Christopher (Department: 1651)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

15 to 23 amino acid residues in defined sequence

C530S324000, C514S013800, C514S002600, C514S012200, C435S184000, C435S212000, C435S218000, C435S219000, C435S183000, C435S222000

Reexamination Certificate

active

06184346

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to peptides derived from Guamerin which inhibit protease activity, more specifically, to peptides inhibiting elastase and subtilisin activity, which are derived from Guamerin, an elastase-inhibiting protein isolated from a Korean leech, Guameri(Hirudo nipponia).
2. Description of the Prior Art
Elastase is a serine protease capable of degrading mainly elastin and also connective tissue proteins such as collagen, cartilage, and fibronectin(see: Reilly, C. et al., Biochem. Biophys. Acta., 621:147-167(1980); Mainardi, C. L. et al., J. Biol. Chem., 255:5436-5441(1980)).
Human leukocyte elastase is stored principally in neutrophils and the stored elastase is released, when neutrophils encounter foreign pathogens or antigens in blood, to degrade them so that body is protected from the harmful factors(see: Weisemann, G. et al., New Engl. J. Med., 303:27-34(1980)). However, uncontrolled secretion of elastase which frequently results from aging of the cells or genetic disorder may cause non-specific proteolysis and trigger destructive processes associated with various chronic diseases such as rheumatoid arthritis, emphysema, and psoriasis(see: Glinski, W. et al., J. Invest. Dermatol., 75:481-487(1980); Snider, G. L., Med. Clin. North. Am., 65:647-666(1981)).
In medical field, for the treatment of said diseases, strenuous efforts have been made in developing an agent which can effectively suppress the activity of elastase which is released abnormally in excess from the tissues of joint cartilage, lung, and skin. As a consequence, elastase-inhibiting proteins have been isolated from a variety of biological sources such as birds including turkeys or ducks, European leeches, and human skin(see: Schalwijk, J. et al., Br. J. Dermatol., 1512:181-186(1986).; Wlodow, O. et al., J. Biol. Chem., 165:14791-14796(1990); Hochstrasser, K. et al., Hopps-Seyler's Z. Physiol. Chem., 362:1369-1375(1981); Seemiller, U. et al., Hopps-Seyler's z. Physiol. Chem., 361:1841-1846(1980)), which were found to be effective for the treatment of said diseases, especially when a medicine containing the protein as an active ingredient was administered directly to the affected parts.
However, the elastase-inhibiting proteins of prior art, except the one isolated from human skin, have had trouble for the use as a medicine, since their specificity for elastase is so low that the activities of other enzymes are possibly inhibited. Moreover, since the said elastase-inhibiting proteins including the one from human skin have an extremely high molecular weight, a serious problem has been frequently encountered that the proteins may be easily denatured by heat, which finally decreases their activities rapidly.
Under the circumstances, there are strong reasons for exploring and developing alternative proteins which inhibit the elastase activity in a specific manner. In this connection, the present inventors have isolated a novel elastase-inhibiting protein named ‘Guamerin’, from a Korean leech, Guameri(Hirudo nipponia) and discovered that Guamerin inhibits the elastase activity specifically, has stronger activity than the conventional elastase-inhibiting proteins, and is also stable under strongly acidic or alkaline condition(see: UK Patent Application GB 2300190A; H. I. Jung et al., J. Biol. Chem., 270(23) :13879-13884(1995)). Accordingly, Guamerin has a distinction over the conventional elastase-inhibiting proteins that: it may not cause untoward effects, when it is administrated as a medicine; and, its chemical nature is so stable that it is not easily denatured in the course of mass production, storage and transport, which naturally eases its practical application.
However, since Guamerin is still large molecule to be practically applied in medicinal use, the inventors have made an effort to develop peptides which contain active sites of Guamerin showing elastase-inhibiting activities permitting its convenient synthesis and use.
SUMMARY OF THE INVENTION
In accordance with the present invention, the inventors discovered that: peptides consisting of 19 amino acids which contain the 36th-methionine of the active site of Guamerin, show elastase-inhibiting activities; and, the said peptides, unlike an intact Guamerin, also inhibit subtilisin activity and elastase activity as well.
A primary object of the invention is, therefore, to provide peptides derived from Guamerin which inhibit elastase and subtilisin activities.
The other object of the invention is to provide dimeric peptides formed by intermolecular disulfide bond between the peptides, which also inhibit elastase and subtilisin activities.


REFERENCES:
patent: 6008320 (1999-12-01), Kang et al.
patent: 28 08 396 (1979-09-01), None
patent: 90/12808 (1990-11-01), None
Kim et al. “Guamerin-derived synthetic inhibitors against elastase and subtilisin,” Protein Pep. Lett. (Oct. 1996) 3(5): 301-308.
Isolation and Characterization of Guamerin, a New Human Leukocyte Elastase inhibitor from Hirudo nipponia, Hyo H. Jung, et al. The Journal of Biological Chemistry vol. 270, No. 23, Issue of June 9, pp. 13879-13884, 1995.

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