Polypeptide and anti-HIV drug prepared therefrom

Details Polypeptide and anti-HIV drug prepared therefrom Polypeptide and anti-HIV drug prepared therefrom

1992-07-01

1996-11-05

Russel, Jeffrey E.

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

A61K 3810, C07K 708

Patent

active

055718922

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to a novel polypeptide or a salt thereof. More detailedly, this invention relates to a novel polypeptide exhibiting a strong affinity to lipopolysaccharides, particularly endotoxins and having an improved antibacterial activity and an improved antiviral activity, a pharmaceutically acceptable salt thereof, and an anti-HIV agent containing the same as an effective ingredient.


BACKGROUND ART

Heretofore, as shown in the following literatures, there have been reported by Nakamura, Iwanaga, Niwa, et al. polypeptides (Tachyplesin and Polyphemusin) exhibiting an affinity to endotoxins and being derived from horseshoe crabs and their pharmacological properties.
(i) J. Biol. Chem., 263, 16709-16713 (1988)
(ii) Published Searched Application 500194/1990
(iii) Chem. Pharm. Bull., 37, 2661-2664 (1989)
(iv) Japanese Laid-Open Patent Publication No. 53799/1990
(v) Japanese Laid-Open Patent Publication No. 152987/1990
(vi) Japanese Laid-Open Patent Publication No. 167230/1990
(vii) J. Blochem., 106, 663-668 (1989)
(viii) Taisha (Metabolism), 26, 301-311 (1989)
As for polypeptides having an affinity to endotoxins isolated from horseshoe crabs (the genus Tachypleus, the genus Lumulus and the genus Carcinoscorpius), 5 structural analogs exist, to the best of researcher's knowledge, and each of them is a polypeptide having a cyclic structure comprising 17 or 18 natural amino acids. Further, these polypeptides mutually exhibit extremely analogous properties, and such a polypeptide is very interesting as one of key substances whereby horseshoe crabs have been able to be adapted to changes of their external environment and preserve their species from ancient times to the present time as a living fossil.
On the other hand, with respect to maintenance of the existence of human beings who have highly differentiated, drugs are being desired which are expected to have a prophylactic or therapeutic effect on an acquired immune deficiency syndrome (AIDS) caused by infection with a human immunodeficiency virus.
The present inventors paid their attention to the above endotoxin-affinitive polypeptides conjectured to have relation to the strong preservability of species on horseshoe crabs, and made a study of a correlation between structural changes on these substances and the anti-human immunodeficiency virus (HIV) activity. As a result, they found novel polypeptides basically different from the common structure of the known endotoxin-affinitive polypeptides of horseshoe crabs, and, to their surprise, it was ascertained that these novel polypeptides have an excellent effect that their anti-HIV activity values are 10 times or more as large as that of a known endotoxin-affinitive polypeptide.


DISCLOSURE OF INVENTION

This invention was reached based on such a finding and relates to a novel polypeptide represented by the following formula (I) (SEQ. ID. NO: 1) ##STR2## [wherein
A.sub.1 denotes a hydrogen atom or one or two amino acid residues of amino acids selected from lysine and arginine,
A.sub.2 independently denotes a tyrosine, phenylalanine or tryptophan residue,
A.sub.3 independently denotes an arginine or lysine residue,
A.sub.4 independently denotes an alanine, valine, leucine, isoleucine, serine, cysteine or methionine residue,
A.sub.5 denots --OH (derived from the carboxyl group) or --NH.sub.2 (derived from the acid-amide group),
Cys denotes a cysteine residue,
Gly denotes a glycine residue,
Lys denotes a lysine residue,
Arg denotes an arginine residue, and
Trp denotes a tryptophan residue; and the cysteine residues at the 3- and 16-positions may be linked through a disulfide linkage (--S--S--), and when the 7- and 12-positions are both cysteine residues, these may be linked through a disulfide linkage (--S--S--)] or a salt thereof.
The novel polypeptide of the invention has a basically important characteristic that although, in the known polypeptides derived from the horseshoe crabs, the amino acid residue at the 6-position is a valine (Val) residue in common, its 6-position is a lysin

REFERENCES:
patent: 5449752 (1995-09-01), Fujii et al.
Leff, Bioworld Today, (Oct. 28, 1994) vol. 5, No. 210 p. 1.
Saag et al., J. of Acquired Immune Def. Synd., vol. 7 Suppl. 2, S2-S11, (1994).
Hammer et al., J. of Acquired Immune Def. Synd., vol. 7 Suppl. 2, (1994) pp. 524-537.
Richman et al., J. of Virology, Mar. 1994, pp. 1660-1666. vol. 68 No. 3.
ASM News vol. 56 No. 7 Jul. 1990 (American Society for Microbiology).
Masuda et al. Biochem. and Biophys. Res. Commun. vol. 189 No. 2 (1992) pp. 845-850.
T. Mula et al. "Primary Structures and Functions of Anti-Lipopolysaccharide Factor and Tachyplesin Peptide Found in Horseshoe Crab Hemocytes," Advances in Experimental Medicine and Biology, vol. 256, 1990, 273-285, New York.
Nakamura et al., "Tachyplesin, a class of Antimicrobial Peptide from the Hemocytes of the Horseshoe Crab (Tachypleus tridentatus)". J. Biol. Chem. vol. 263, No. 32, Nov. 15, pp. 16709-16713, (1988).
Akaji et al., "Studies on Peptides. CLXVIII. Syntheses of Three Peptides Isolated from Horseshoe Crab Hemocytes, Tachyplesin I, Tachyplesin II, and Polyphemusin I". Chem. Pharm. Bull. 37 2661-2664 (1989).
Miyata et al., "Antimicrobial Peptides, Isolated from Horseshoe Crab Hemocytes, Tachyplesin II, and Polyphemusins I and II: Chemical Structures and Biological Activity". J. Biochem. 106, 663-668 (1989).
Taisha "LPS-binding protein and peptide, esp. chem. structures and biol. activities thereof". Metabolism, vol. 26, No. 5 429-439 (1989).

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