Family of peptides known as xenoxins

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai

Reexamination Certificate

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C424S184100, C424S185100, C530S300000, C530S350000, C435S069100

Reexamination Certificate

active

06277822

ABSTRACT:

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, Neuroendocrine Perspectives, E. E. Müller 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 wound 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 is 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
1
with Cys
3
, Cys
2
with Cys
4
, Cys
5
with Cys
6
and Cys
7
with Cys
8
;
b. contains 0 to 3 amino acids on the N-terminal side of Cys
1
, 9 to 14 amino acids between Cys
1
and Cys
2
, 3 to 7 amino acids between Cys
2
and Cys
3
, 11 to 18 amino acids between Cys
3
and Cys
4
, 1 to 6 amino acids between Cys
4
and Cys
4
, 7 to 15 amino acids between Cys
5
and Cys
6
, no amino acid between Cys
6
and Cys
7
, 3 to 5 amino acids between Cys
7
and Cys
8
and 0 to 10 amino acids on the C-terminal side of Cys
8
; and
C. displays an identity of amino acids, after alignment, of at least 40% with the amino acid sequence identified under the number SEQ ID NO: 3,
or a fragment derived from this sequence.
The term xenoxin refers to a small basic protein displaying the features described.
In the context of the present invention, the number appearing as index against a cysteine residue indicates its position relative to the other cysteines in said xenoxin in the N- to C-terminal direction. Thus Cys
1
refers to the first cysteine appearing in a xenoxin according to the invention on the N-terminal side.
The present invention also relates to the intermediate peptides which have not yet adopted their folded conformation but which contain at least 8 cysteines capable of linking to one another through 4 disulphide bridges according to the arrangement Cys
1
with Cys
3
, Cys
2
with Cys
4
, Cys
5
with Cys
6
and Cys
7
with Cys
8
.
Thus, the present invention relates to a basic peptide which is characterized in that it comprises an amino acid sequence which:
a. contains at least 8 cysteines which, when the peptide adopts its folded conformation, are linked through 4 disulfide bridges according to the arrangement Cys
1
with Cys
3
, Cys
2
with Cys
4
, Cys
5
with Cys
6
and Cys
7
with Cys
8
;
b. contains 0 to 3 amino acids on the N-terminal side of Cys
1
, 9 to 14 amino acids between Cys
1
and Cys
2
, 3 to 7 amino acids between Cys
2
and Cys
3
, 11 to 18 amino acids between Cys
3
and Cys
4
, 1 to 6 amino acids between Cys
4
and Cys
5
, 7 to 15 amino acids between Cys
5
and Cys
6
, no amino acid between Cys
6
and Cys
7
, 3 to 5 amino acids between Cys
7
and Cys
8
and 0 to 10 amino acids on the C-terminal side of Cys
8
; and
c. displays an identity of amino acids, after alignment, of at least 40% with the amino acid sequence identified under the number SEQ ID NO: 3,
or fragment derived from this sequence.
Preferred peptides of the present invention contain two amino acids on the N-terminal side of Cys
1
, 10 to 13 amino acids between Cys
1
and Cys
2
, 4 to 6 amino acids between Cys
2
and Cys
3
, 12 to 17 amino acids between Cys
3
and Cys
4
, 1 to 5 amino acids between Cys
4
and Cys
5
, 8 to 14 amino acids between Cys
5
and Cys
6
, no amino acid between Cys
6
and Cys
7
, 4 amino acids between Cys
7
and Cys
8
and 2 amino acids on the C-terminal side of Cys
8
.
Other peptides, also preferred, of the present invention display an identity of amino acids of at least 50%, as a special preference of at least 60% and advantageously of at least 70%, with the amino acid sequence identified under the number SEQ ID NO: 3.
Especially preferred peptides according to the invention are the xenoxins which are characterized in that they comprise an amino acid sequence which:
a. contains at least 8 cysteines which are linked through 4 disulfide bridges according to the arrangement Cys
1
with Cys
3
, Cys
2
with Cys
4
, Cys
5
with Cys
6
and Cys
7
with Cys
8
;
b. contains 0 to 3 amino acids on the N-terminal side of Cys
1
, 13 amino acids between Cys
1
and Cys
2
, 6 amino acids between Cys
2
and Cys
3
, 12 amino acids between Cys
3
and Cys
4
, 5 amino acids between Cys
4
and Cys
5
, 14 amino acids between Cys
5
and Cys
6
, no amino acid between Cys
6
and Cys
7
, 4 amino acids between Cys
7
and Cys
8
and 0 to 10 amino acids on the C-terminal side of Cys
8
; and
c. displays an identity of amino acids, after alignment, of at least 80%, and preferably 90%, with the amino acid sequence identified under the number S

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