Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1994-06-02
1996-02-06
Warden, Jill
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530324, A61K 3800, C07K 500, C07K 700, C07K 1700
Patent
active
054895758
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new polypeptides having bacteriocidal activity in that they are capable of killing certain bacteria, particularly gram-negative ones. The invention also covers pharmaceutical compositions and methods of use for the inhibition of bacterial growth.
The small intestine is an important endocrine organ and a number of physiologically active peptides have been initially isolated from porcine tissue (Mutt, V., Chemica Scripta 26B, 191-207 (1986)). During normal healthy conditions, the upper part of the small intestine contains few bacteria. Below the duodenum the concentration of bacteria progressively increases until the maximum, 10.sup.11 bacteria per g of feces, is reached in the large intestine. It is remarkable that such a mass of bacteria can coexist with a delicate host organ. Small basic peptides called cecropins play an important role in insect immunity (Boman, H. G. & Hultmark, D., D.Ann.Rev.Microbiol. 41, 103-126 (1987)) and structurally unrelated peptides called magainins (Zasloff, M., Proc.Natl. Acad. Sci. USA, 84, 5449-5453 (1987)) protect the frog skin from infections. Another group of antibacterial peptides, the defensins were first isolated-from mammalian granulocytes (Selstedt, M. E., Szklarek, D. & Lehrer, R. I. Infect. Immun. 45, 150-154 (1984)) and neutrophils (Selstedt, M. E. , Brown, D. M., DeLange, R. J., Harwig, S. S. & Lehrer, R. I., J.Biol. Chem 260, 4579-4584 (1985)) and recently also from insects (Matsuyama, K. & Natori, S. J.Biol.Chem. 263, 17112-17116 (1988); Lambert, J. et al. Proc.Natl.Acad. Sci. USA 86, 262-266 (1989)). In addition, bovine neutrophils have been found to contain bactenecins (Romeo, D., Skerlavaj, B., Bolognesi, M & Gennaro, R. J.Biol.Chem. 263, 9573-9575 (1988), another small basic peptide. Both defensins and the small bactenecin contain one or more disulfide bridges while cecropins and magainins are cysteine-free. Frank et al (J. Biol. Chem. 265:18871-18874) have described two large bactenicins with high contents of proline and arginine and without cysteine.
The present invention has for an object to provide new bactericidal polypeptides capable of inhibiting bacterial growth, in particular the growth of gram negative bacteria. In this disclosure the term "inhibiting" also includes the killing of bacteria.
Another object of the invention is to provide compositions containing as an active constituent such polypeptides.
Yet another object of the invention is to provide a method of treatment directed to inhibition of bacterial growth in animals, in particular mammals including man.
For these and other objects which will be clear from the following disclosure the invention provides a polypeptide having the amine acid sequence [SEQ ID NO.:1]:
Arg-Arg-Arg-Pro-Arg-Pro-Pro-Tyr-Leu-Pro-Arg-Pro-Arg-Pro-Pro-Pro-Phe-Phe-Pro -Pro-Arg-Leu-Pro-Pro-Arg-Ile-Pro-Pro-Gly-Phe-Pro-Pro-Arg-Phe-Pro-Pro-Arg-Ph e-Pro,
and the invention also includes functional derivatives such as a few conservative amine acid replacements and the C-terminal amide.
The polypeptide of the present invention and its functional derivatives are all therapeutically useful, particularly as antibacterial agents, Thus, they are capable of inhibiting growth of bacteria or killing bacteria, in particular gram-negative bacteria making them useful for different therapeutic purposes. This will be further illustrated by specific examples which are given below.
The active polypeptide according to the present invention can be formulated for use in human or veterinary medicine for therapeutic or profylactic use. The active preparations are normally administered orally, rectally or parenterally, such as by injection in the form of a pharmaceutical preparation or composition comprising the active constituents in combination with a pharmaceutically acceptable carrier which may be solid, semi-solid or liquid, or contained in a capsule, such as when orally administered. The administration may also take the form of topical application. As examples of pharmaceutical preparations there may be menti
REFERENCES:
patent: 5096886 (1992-03-01), Boman et al.
Proc. Natl. Acad. Sci USA, "Antibacterial Peptides from Pig Intestine: Isolation of a Mammalian Cecropin", Jong-Youn Lee et al., vol. 86, pp. 9159-9162, Dec. 1989.
Boman Hans G.
Jornvall Hans
Lee Jong-Youn
Mutt Viktor
Boman Hans G.
Huff Sheela J.
Warden Jill
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