Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-09-14
2000-02-08
Wax, Robert A.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530350, 530330, C07K 1481, C07K 412, C07K 510, A61K 3855
Patent
active
060228555
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to endoproteases, particularly a novel endoprotease termed furin endoprotease. The invention also relates to inhibitors of furin endoprotease activity. In particular, the invention relates to novel variants of .alpha..sub.1 -antitrypsin that specifically inhibit furin endoprotease activity. The invention also provides methods for using such inhibitors to attenuate or prevent biological proteolytic maturation of bioactive proteins and peptides in vivo and in vitro, in particular viral proteins and bacterial toxins. Therapeutic methods and pharmaceutical compositions of such inhibitors are also provided directed towards the alleviation and treatment of disease having microbiological etiology.
2. Background of the Related Art
Most biologically active peptides and proteins are synthesized initially as larger, inactive precursor proteins that are endoproteolytically cleaved during transit through the secretory pathway in the Golgi apparatus in cells expression such proteins (see Barr, 1991, Cell 66: 1-3 for review). This system comprises an important common mechanism required for synthesis of biologically active proteins and peptides in yeast (Fuller et al., 1988, Ann. Rev. Physiol. 50: 345-362), invertebrates (Scheller et al., 1983, Cell 32: 7-22) and mammalian cells (Sossin et al., 1989, Neuron 2: 1407-1417). Examples of proteins produced in vivo by exocytotic transport through the Golgi are precursors of peptide hormones, neuropeptides, growth factors, coagulation factors, serum albumin, cell surface receptors, and adhesion molecules.
Morrison et al., 1985, J. Virol. 53: 851-857 disclose that F protein of Newcastle disease virus is processed through the exocytotic transport pathway in infected cells.
Perez & Hunter, 1987, J. Virol. 61: 1609-1614 disclose that the Rous sarcoma virus (RSV) glycoprotein is processed through the exocytotic transport pathway in infected cells.
Yamada et al., 1988, Virology 165: 268-273 disclose that F protein of mumps virus is processed through the exocytotic transport pathway in infected cells.
Randolph et al., 1990, Virology 174: 450-458 disclose that the prM protein of flaviviruses is processed through the exocytotic transport pathway in infected cells.
A common structural feature of molecules processed through the exocytotic transport pathway is the presence of basic residues or pairs of basic residues at the proteolytic processing site in the molecule. Examples include serum factors (Factor IX; Bentley et al., 1987, Cell 45: 343-348; proalbumin; Knowles et al., 1980, Science 209: 497-499; pro-von Willibrand factor; Bonthron et al., 1986, Nature 324: 270-273), viral polyproteins (human immunodeficiency virus (HIV) gp160; McCune et al., 1988, Cell 53: 55-67; RSV envelope protein; Perez & Hunter, 1987, J. Virol. 61: 1609-1614; yellow fever virus protein; Rice et al., 1985, Science 229: 726-733; measles virus protein; Richardson et al., 1986, Virology 155: 508-523; mumps virus protein; Waxham et al., 1987, Virology 159: 381-389; human cytomegalovirus protein; Spaete et al., 1990, J. Virol. 64: 2922-2931; varicella zooster virus protein; Keller et al., 1986, Virology 152: 181-191), growth factors (pre-protransforming growth factor .beta.; Gentry et al., 1988, Molec. Cell. Biol. 8: 4162-4168; epidermal growth factor; Gray et al., 1983, Nature 303: 722-725; pro-.beta.-nerve growth factor (NGF); Edwards et al., 1988, Molec. Cell Biol. 8: 2456-2464), receptors (insulin receptor; Yoshimasa et al., 1988, Science 240: 784-787); and bacterial toxins (see Stephen & Pietrowski, 1986, Bacterial Toxins, 2d ed. (Amer. Soc. Microbiol. Washington, D.C.) for review; anthrax toxin; Singh et al., 1989, J. Biol. Chem. 264: 11099-11102). The proteolytic processing site has been identified in some of these molecules.
Berger & Shooter, 1977, Proc. Natl. Acad. Sci. USA 74: 3647-3651 disclose the sequence -RSKR- (SEQ ID NO.: 1) at the proteolytic processing site of pro-.beta.-NGF.
Bentley et al., 1986, ibid. disclose the seque
REFERENCES:
patent: 4732973 (1988-03-01), Barr et al.
patent: 5604201 (1997-02-01), Thomas et al.
Oda, K. et al. "Proteolytic cleavages of proalbumin and complement pro-C3 in vitro by a truncated soluble form of furin, a mammalian homologue of the yeast Kex2 protease" Biochemical and Biophysical Research Communications (Dec. 30, 1992), vol. 189, No. 3.
George, P.M. et al. "Characterization of antithrombins produced by active site mutagenesis of human alpha 1-antitrypsin expressed in yeast" Blood (Feb. 1989), vol. 73, No. 2, pp. 490-496.
Molloy, S.S. et al. "Human furin is a calcium-dependent serine endoprotease that recognizes the sequence Arg-X-X-Arg and efficiently cleaves anthrax toxin protective antigen" Journal of Biological Chemistry (Aug. 1992), vol. 267, No. 23, pp. 16396-16402.
Klimpel, K.R. et al. "Cleavage of diptheria toxin and the protective antigen of Bacillus-anthracis by the eukaryotic endoprotease furin" Abstracts of the General Meeting of the American Society for Microbiology (May, 1992), vol. 92, p. 31.
Anderson Eric D.
Hayflick Joel S.
Thomas Gary
Thomas Laurel
Lau Kawai
Oregan Health Sciences University
Wax Robert A.
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