Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-06-13
1998-07-07
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530327, A61K 3800, A61K 3804, C07K 500, C07K 700
Patent
active
057768994
DESCRIPTION:
BRIEF SUMMARY
1. FIELD OF THE INVENTION
This invention relates to a novel polypeptide(s) or a pharmaceutically acceptable salt thereof exhibiting a strong affinity to lipopolysaccharides, particularly endotoxins. The polypeptide may be used in a pharmaceutical composition as an anti-viral agent (e.g. anti-HIV agent).
2. BACKGROUND OF THE INVENTION
Two families of antimicrobial polypeptides have been isolated from horseshoe crabs which exhibit an affinity to endotoxins (see, for example, Shigenaga et al., 1990, J. Biol. Chem. 265:21350-21354; Kawano et al., 1990, J. Biol. Chem. 265:15365-15367; Muta et al., 1990, J. Biochem. 108:261-266; Japanese Laid-Open Patent Publication No. 167230/1990; Japanese Laid-Open Patent Publication No. 152987/1990; Japanese Laid-Open Patent Publication No. 53799/1990; Published Searched Application 500194/1990; Miyata et al., 1989, J. Biochem. 106:663-668; Akaji et al., 1989, Chem. Pharm. Bull. 37:2661-2664; Tokunaga and Iwanaga, 1989, Taisha(Metabolism) 26:429-439 ; Shieh et al., 1989, FEBS Lett. 252:121-124; and Nakamura et al., 1988, J. Biol. Chem. 263:16709-16713).
One family, the tachyplesin family has been isolated from the Japanese horseshoe crab Tachypleus. Three tachyplesins, I, II, and III have been identified. A second family, the polyphemusin family has been isolated from the American horseshoe crab, Limulus polyphemus. Two polyphemusins, I and II have been identified; their amino acid sequences are shown in FIG. 1.
The polypeptides in both families consist of 17 or 18 amino acid residues and have four conserved regions in common and two disulfide bridges (see FIG. 1).
Both tachyplesins and polyphemusins have been found to inhibit the growth of both Gram-negative and -positive bacteria at low concentrations as well as fungi, such as Candida albicans and form complexes with bacterial lipopolysaccharides (Shigenaga et al., 1990, J. Biol. Chem. 265:21350-21354 and Muta et al., 1990, J. Biochem. 108:261-266). Also, the polypeptides in a tachyplesin family have been found to exhibit some inhibition activity for virus, such as Influenza virus, vesicular stomatitis virus (Murakami et al., 1991, Chemotherapy, 37, 327-334) or human immunodeficiency virus (Morimoto, et al., 1991, Chemotherapy, 37, 206-211). It is very interesting that such a polypeptide with above properties may be one of the key substances which enables the horseshoe crab to adapt with changes in their external environment and to preserve their species from ancient times to now as a living fossil.
On the other hand, with respect to the survival of the highly evolved human beings, development of such drugs is extremely longing that have a prophylactic or therapeutic effect on acquired immune deficiency syndrome (AIDS) caused by infection with human immunodeficiency virus (HIV).
Present inventors and coresearchers have been studied a correlation between molecular structure and anti-HIV activity on the polypeptides with changing or modifying the amino acid of components, taking notice of these polypeptides which are related to the long preservation of the horseshoe crabs. As a result, the past new polypeptides had been invented by us, fundamentally different from the common structure of such the known polypeptides of the horseshoe crabs.
Surprisingly, it was found that these past new polypeptides have an excellent bioactivity whose anti-HIV values are at least 5 times or more higher than that of a known polypeptides of the horseshoe crabs.
Following references had be seen, Nakashima et al., 1992, Antimicrob. Agents Chemother., 36, 1249-1255 ; Masuda et al., 1992, Biochem. Biophys. Res. Commun., 189, 845-850 ; Tamamura et al., 1993, Chem. Pharm. Bull., 41, 978-980 ; Tamamura et al., 1993, Biochim. Biophys. Acta, 1163, 209-216 ; Masuda et al., 1992, J. Pharmacobio. Dyn., 15, s-90 ; International Laid-Open Publication WO 92/04374 ; Japanese Laid-Open Patent Publication No.163298/1993. the best mode compound of the representatives.) Having examined the structural requirements for exhibiting the activity of the new polypepti
REFERENCES:
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patent: 5571892 (1996-11-01), Fujii et al.
Akaji, 1989, "Studies on Peptides. CLXVIII. Synthesis of Three Peptides Isolated from Horseshoe Crab Hemocytes, Tachyplesin I, Tachyplesin II, and Polyphemusin I", Chem. Pharm. Bull. 37: 2661-2664.
Kawano et al., 1990, "Antimicrobial Peptide, Tachyplesin I, Isolated from Hemocytes of the Horeshoe Crab", The Journal of Biological Chemistry 265: 15365-15367.
Legendre and Szoka, 1993, "Cyclic amphipathic peptide-DNA complexes mediate high-efficiency transfection of adherent mammalian cells", Proc. Natl. Acad. Sci. USA 90: 893-897.
Masuda et al., 1992, "Structure-Activity Relationships of tachyplesin analogs as anti-HIV agent" J. Pharmacobio-Dyn. 15: s-90.
Masuda et al., 1992, "A Novel Anti-HIV Synthetic Peptide, T-22 Research Communications 189:845-850.
Matsuzaki et al., 1991, "Interactions of an antimicrobial peptide, tachyplesin I, with lipid membranes" Biochimica and Biophysica Acta 1070: 259-264.
Miyata et al., 1989, "Antimicrobial Peptides, Isolated from Horseshoe Crab Hemocytes, Tachyplesin II and Polyphemusins I and II:Chemical Structures and Biological Activity", J. Biochem. 106: 663-668.
Morimoto, 1991, "Inhibitory Effect of Tachyplesin I on the Proliferation of Human Immunodeficiency Virus in vitro", Chemotherapy 37: 206-211.
Murakami et al., 1991, "Direct Inactivation of Tachyplesin I and Its Isopeptides from Horseshoe Crab Hemocytes", Chemotherapy 37: 327-334.
Muta et al., 1990, Tachplesins Isolated from Hemocytes of Southeast Asian Horseshoe Crabs (Carcinoscorpius rotundicauda and Tachypleus gigas): Identification of a New Tachyplesin Tachyplesin, III, and a Processing Intermediate as its Precursor, J. Biochem. 108: 261-266.
Nakamura et al., 1988, Tachyplesin, a Class of Antimicrobial Peptide from the Hemocytes of the Horseshoe Crab (Tachpleus tridentatus), The Journal of Biological Chemistry 263:16709-16713.
Nakashimura et al., 1992, "Anti-Human Immunodeficiency Virus Activity of a Inhibitor of Virus-Cell Fusion", Antimicrobial Agents and Chemotherapy, Jun. 1992: 1249-1255.
Shieh et al., 1989, "Synthsis and properties of tachyplesin I, a lipopolysaccharide-binding peptide, from Tachypleus tridentatus", Febs Letters 252: 121-124.
Shigenaga et al., 1990, "Antimicrobial Tachyplesin Peptide Precursor", The Journal of Biological Chemistry 265: 21350-21354.
Tamamura, 1993, "A Comparative study of the solution structures of tachyplesin I and a novel anti-HIV synthetic peptide, T22(Tyr.sup.5,12, Lys.sup.7 -polylphemusin II), determined by nuclear magnetic resonance", Biochimica and Biophysica Acta 1163: 209-216.
Tokunaga and Iwanaga, 1989, "LPS-binding proteins and peptides", Taisha (Metabolism) 26: 429-439.
Yonezawa et al, 1992, "Binding of Tachyplesin I to DNA Revealed by Footprinting Analysis: Significant Contribution of Secondary Structure to DNA Binding and Implication for Biological Action", Biochemistry 31: 2998-3004.
Matsumoto Akiyoshi
Waki Michinori
Harle Jennifer
Seikagaku Corporation
Tsang Cecilia J.
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