78 residue polypeptide (NK-lysine) and its use

Details 78 residue polypeptide (NK-lysine) and its use 78 residue polypeptide (NK-lysine) and its use

1996-12-04

1999-11-09

Feisee, Lila

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

530200, 530350, C07K 1400, C07K 14435

Patent

active

059814691

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a new polypeptide, its therapeutic use, pharmaceutical compositions containing same as an active ingredient and a method for inhibiting microbial growth.
The upper part of the small intestine is under normal healthy conditions almost sterile and could therefore be expected to produce antimicrobial peptides. In 1987 a program was started for the identification of such peptides using the large scale fractionation scheme devised for the isolation of peptide hormones produced in the porcine small intestine [Mutt, V. 1986. Question answered and raised by work on the chemistry of gastrointestinal and cerebrogastrointestinal hormonal polypeptides. Chem Scr. 26B: 191-207]. This project has earlier yielded five antibacterial peptides, the present paper describes the sixth one. The two first peptides, cecropin P1 [Lee, J.-Y., A. Boman, S. Chuanxin, M. Andersson, H. Jornvall, V. Mutt and H. G. Boman. 1989. Antibacterial peptides from pig intestine: Isolation of a mammalian cecropin. Proc. Natl. Sci. USA. 86: 9159-9162] and PR-39 [Agerberth, B., J.-Y. Lee, T. Bergman, M. Carlquist, H. G. Boman, V. Mutt and H. Jornvall, 1991. Amino Acid Sequence of PR-39--Isolation from Pig Intestine of a New Member of the Family of Proline-Arginine-Rich Antibacterial Peptides. Eur J Biochem. 202: 849-854], showed both potent activity against several Gram-negative bacteria. They also act on Bacillus megaterium but they do not act on other Gram-positive bacteria like Staphylococcus. Cecropin P1 was clearly related to the insect cecropins and was related to two proline-rich peptides from bovine phagocytes. The next three peptides to be identified [Agerberth, B., A. Boman, M. Andersson, H. Jornvall, V. Mutt and H. G. Boman. 1993. Isolation of three antibacterial peptides from pig intestine: gastric inhibitory polypeptide (7-42), diazepam-binding inhibitor (32-86) and a novel factor, peptide 3910. Eur. J. Biochem. 216: 623-629] were active against B.megaterium but not against E.coli and two of these turned out to be derived from earlier known hormones, GIP (gastric inhibitory polypeptide) and DB1 (diazepam-binding inhibitor).
The intestine is an organ rich in blood vessels and peptides isolated from intestine can originate from blood cells. Thus, PR-39 was recently shown to be produced in the pig bone marrow rather than in the intestine [Storici, P. and M. Zanetti 1993. A cDNA derived from pig bone marrow cells predicts a sequence identical to the intestinal antibacterial peptide PR-39. Biochem. Biophys. Res. Comm. 196: 1058-1065] and this applies also to the protegrin PG-2 [Storici, P. and M. Zanetti, 1993. A cDNA derived from pig bone marrow cells predicts a sequence identical to the intestinal antibacterial peptide PR-39. Biochem. Biophys. Res. Comm. 196: 1058-1065] a peptide earlier isolated from pig phagocytes. Defensin-like peptides, cryptins, have been isolated from murine small intestine and human Paneth cells express a gene for a definsin-like peptide.
Defensins were earlier found in circulating phagocytes of a number of mammals [Lehrer, R. I. and Ganz, T. 1992. Defensins--Endogenous Antibiotic Peptides from Human Leukocytes. In Secondary Metabolites: Their Function and Evolution, p 276-293, Ciba Foundation Symposia No. 171. John Wiley & Sons Ltd., Chichester, PO19 1UD, UK]. Bovine phagocytes contain a number of different peptide antibiotics: A small dodeca peptide with two cysteines called bactenecin [Romeo, D., B. Skerlavaj, M. Bolognesi and R. Gennaro, 1988. Structure and bactericidal activity of an antibiotic dodecapeptide purified from bovine neutrophils. J.Biol.Chem. 263: 9573-9575], two larger Proline-rich peptides, Bac5 and Bac7, [Frank, R. W., R. Gennaro, K. Schneider, M. Przybylski and D. Romeo. 1990. Amino acid sequences of two proline-rich bactenecins Antimicrobial peptides of bovine neutrophils. J.Biol.Chem. 265: 18871-18874] and a tryptophan-rich peptide, indolicidin [Selsted, M. E., M. J. Novotny, W. L. Morris, Y. Q. Tang, W. Smith and J. S. Cullor, 1992. Indolicidin, a Novel Bacteri

REFERENCES:
Lehrer et al. (1993) Annu. Rev. Immunol. 11 :105-128.

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