Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-12-28
2000-06-20
Davenport, Avis M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 2, 514 12, 530324, 530300, 4241841, 4241851, 435 4, 435 691, A61K 3800, A61K 3900, C07K 500, C07K 700
Patent
active
06077827&
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a family of peptides known as xenoxins, to the members of the peptide family as well as to methods for preparing them and to the corresponding DNA sequences. It also relates to pharmaceutical compositions containing said xenoxins as well as to diagnostic kits containing them or containing anti-xenoxin antibodies.
A large number of peptides with various biological functions have already been isolated from the skin or skin secretions of amphibia (V. Erspamer and P. Melchiorri, Neutoendocrine Perspectives, E. E. Muller and McLeod, Eds. (Elsevier Science Publishers B.V.) 2, (1983), p 37; C. L. Bevins et al.; Ann. Rev. Biochem. 59; (1990); p 395). From the outset, it was found that several of these peptides were very similar or even identical to hormones and neutrotransmitters of mammals (V. Erspamer et al., Trends Pharmacol. Sci. 1, (1980), p 391).
Thus, frog's skin and skin secretions is [sic] held to be a source of peptides with advantageous pharmacological or antibiotic properties. More especially, the skin of Xenopus laevis, a frog of African origin, contains large concentrations of various peptides.
The biological role which may be performed by these peptides which are to be found in the matter secreted by the glands and skin of Xenopus laevis is only partially known. On the one hand the secretions might have a protective function since the secreted matter would appear to be harmful to predators. On the other hand, the secreted matter contains peptides which limit the growth of bacteria and fungi, and which might hence behave as antibiotics on the wet skin of the frog or combat infections during would healing.
These antibiotic peptides contain, in general, between 21 and 26 amino acids, are basic and are free from tyrosine. The identity of the amino acid sequences of the different antibiotic peptides is often very limited. In contrast, these peptides have their amphipathic alpha-helical conformation in common. In respect of the signal sequences of approximately 20 amino acids, the identity of the amino acid sequences is only 55%. However, conserved segments are to be found, common to the signal sequences of the different antibiotic peptides. Furthermore, they all share an N-terminal Arg-Xaa-Val-Arg sequence which is considered to the site of action of a common maturation enzyme.
As other examples of peptides isolated and characterized in Xenopus laevis, there may be mentioned caerulein, a member of the cholecystokinin/gastrin peptide family (Anastasi et al., Brit. J. Pharmacol. 38, (1970), p 221); spasmolysin I and II (W. Hoffmann, J. Biol. Chem. 263 (16), (1988), p 7686); thyrotropin releasing peptide (K. Richter et al., EMBO J. 3(3), (1984), p 617) and xenopsin (K. Araki et al., chem. Pharmacol. Bull. 21 (12), (1973), p 2801). Most of these peptides are members of a peptide family which contains, inter alia, analogous peptides of mammalian origin. Bombesin and kassinin, for example, have been used as reference to identify gastrin releasing peptide and substance K, respectively, in mammals (C. L. Bevins et al, see above). In point of fact, the matter secreted by frog's skin contains peptides in copious amounts, while the analogous peptide in mammals if often present only in small amounts. Thus, the frog peptides lend themselves to the identification of useful mammalian peptides.
The present invention relates to a new family of peptides which have been named xenoxins and which possess valuable pharmaceutical properties, and especially the property of influencing the functioning of transmembrane ion channels while not displaying neurotoxic activity. Furthermore, it is thought that these peptides would have the advantageous property of abolishing the effects of activin.
More especially, the present invention relates to a xenoxin which is characterized in that it comprises an amino acid sequence which:
a. contains at least 8 cysteines (Cys) which are linked through 4 disulfide bridges according to the arrangement Cys.sup.1 with Cys.sup.3, Cys.sup.2 with Cys.sup.4, Cys.sup.5 w
REFERENCES:
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Brake, Anthony J. et al, ".alpha.-Factor-directed synthesis and secretion of mature foreign proteins in Saccharomyces cerevisiae." Proceedings of the National Academy of Sciences of USA, vol. 81, Aug. 1984, Washington. D.C., pp. 4642-4646.
Reichhart, Jean-Marc et al, "Expression and secretion in yeast of active insert defensin, an inducible antibacterial peptide from the fleshfly Phormia terranovae." Invertebrate Reproduction and Development, vol. 21, No. 1, 1992, pp. 15-24.
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Kolbe, Hanno V.J. et al, "Xenoxins, a family of peptides from dorsal gland secretion of Xenopus laevis related to snake venom cytotoxins and neurotoxins." Journal of Biological Chemistry, vol. 268, No. 22, Aug. 5, 1993, Baltimore, pp. 16458-16464.
Dimarcq, Jean-Luc et al, "Insect immunity: expression of the two major inducible antibacterial peptides, defensin and diptericin, in Phormia terranovae." EMBO Journal, vol. 9, No. 8, 1990, Eynsham, Oxford, pp. 2507-2515.
Inoue, Seiji et al, "Amino acid sequence of a cytotoxin-like basic protein with low cytotoxic activity from the venom of the Thailand cobra Naja naja siamensis." FEBS Letters, vol. 218, No. 1, Jun. 1987, Amsterdam, pp. 17-21 .
Achstetter Tilman
Kolbe Hanno V. J.
Kreil Gunther
Rasmussen Ulla B.
Davenport Avis M.
Transgene S.A.
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