Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-05-19
2003-06-03
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S015800, C530S300000, C530S327000, C530S328000, C530S412000
Reexamination Certificate
active
06573243
ABSTRACT:
This application is a 371 of PCT/JP98/03730, filed Aug. 24, 1998, which claims the priority of Japan JP9-241699, filed Aug. 25, 1997
TECHNICAL FIELD
The present invention relates to novel neuropeptides and more specifically to peptides obtained from the venoms of the solitary wasps
Anoplius samariensis
and
Batozonellus maculifrons
, and analogous peptides thereof.
BACKGROUND ART
Since solitary wasp species such as thread-waisted wasps and pompilid wasps paralyze other insects with their venom, it is believed that the venom contain substances that act on the nervous system. In fact, peptides called mastoparans have been isolated from a certain kind of solitary wasp, and these peptides are used as useful compounds for the study of information transmission system of the living body.
On the other hand, various compounds have been isolated in the studies on spider toxins, and it has been confirmed that their effect of paralyzing nerves is based on their inhibitory action on glutamate receptors. Glutamic acid is known to play an important role as an excitatory neurotransmitter mediated by glutamate receptors in the central nervous system (e.g. brain, spinal cord) of mammals, and the synapses of insects and crustaceans. And further, it is known that excess glutamic acid causes over-excitation of nerve cells resulting in death of the nerve cells. Therefore, enhancement of the function of glutamate receptors and conversely temporary blocking of their function are believed to provide therapeutic benefits on cerebral nerve diseases associated with glutamic acid.
DISCLOSURE OF THE INVENTION
Accordingly, the object of the present invention is to find, in the venom of the solitary wasps, substances that act on the glutamate receptor or substances that promote or inhibit the release of glutamic acid, and to apply them to medical therapeutic purposes.
In order to achieve the above object, the present inventors have isolated a peptide (1) represented by SEQ ID NO: 1:
H-Arg-Ile-Lys-Ile-Gly-Leu-Phe-Asp-Gln-Leu-Ser-Lys-Leu-NH
2
(1)
and a peptide (97) represented by SEQ ID NO: 2:
H-Arg-Ile-Lys-Ile-Gly-Leu-Phe-Asp-Gln-Leu-Ser-Arg-Leu-NH
2
(97)
from the venom sac extracts of solitary wasps
A. samariensis
and
B. maculifrons
, on the basis of the ability to enhance or block the neurotransmission through the neuron synapses of lobster's walking leg.
Furthermore, peptides related to the above peptides (1) and (97) were synthesized by the conventional solid phase method and their structure-activity relationship was examined. As a result, it was found that the peptides represented by the amino acid sequence formula (A):
H-X
1
-X
2
-X
3
-X
4
-Gly-X
6
-X
7
-Asp-Gln-R (A)
wherein:
R is basically NH
2,
which also may be -Leu-NH
2
, -Leu-Ser-NH
2
, -Leu-Ser-Lys-NH
2
, -Leu-Ser-Arg-NH
2
, -Leu-Ser-Lys-Leu-NH
2
, (SEQ ID NO:3) or -Leu-Ser-Arg-Leu-NH
2
(SEQ ID NO:4),
X
1
and X
3
are basic amino acid residues;
X
2
, X
4
and X
6
are aliphatic amino acid residues; and
X
7
is an aromatic amino acid residue, can show the above-mentioned activity.
The basic amino acid residues X
1
and X
3
include arginine or lysine residue, the aliphatic amino acid residues X
2
, X
4
and X
6
include leucine or isoleucine residue, and the aromatic amino acid residue X
7
includes phenylalanine, tyrosine, or tryptophan residue.
Accordingly, the present invention provides, as a neuro-peptide, a peptide represented by the amino acid sequence formula (A):
H-X
1
-X
2
-X
3
-X
4
-Gly-X
6
-X
7
-Asp-Gln-R (A)
wherein:
each of X
1
and X
3
independently represents Arg or Lys, each of X
2
, X
4
and X
6
independently represents Ile or Leu, and X
7
represents Phe, Tyr or Trp; and
R represents —NH
2
, -Leu-NH
2
, -Leu-Ser-NH
2
, -Leu-Ser-Lys-NH
2
, -Leu-Ser-Arg-NH
2
, -Leu-Ser-Lys-Leu-NH
2
, (SEQ ID NO:3) or -Leu-Ser-Arg-Leu-NH
2
(SEQ ID NO:4);
and a salt thereof.
As an embodiment, the present invention provides a peptide represented by the amino acid sequence formula (B):
H-X
1
-X
2
-X
3
-X
4
-Gly-X
6
-X
7
-Asp-Gln-NH
2
(B)
wherein:
each of X
1
and X
3
independently represents Arg or Lys, each of X
2
, X
4
and X
6
independently represents Ile or Leu, and X
7
represents Phe, Tyr or Trp;
and a salt thereof.
As another embodiment, the present invention provides a peptide represented by the amino acid sequence formula (C):
H-X
1
-X
2
-X
3
-X
4
-Gly-X
6
-X
7
-Asp-Gln-Leu-NH
2
(C) (SEQ ID NO:200)
wherein:
each of X
1
and X
3
independently represents Arg or Lys, each of X
2
, X
4
and X
6
independently represents Ile or Leu, and X
7
represents Phe, Tyr or Trp;
and a salt thereof.
As a further embodiment, the present invention provides a peptide represented by the amino acid sequence formula (D):
H-X
1
-X
2
-X
3
-X
4
-Gly-X
6
-X
7
-Asp-Gln-Leu-Ser-NH
2
(D) (SEQ ID NO:199)
wherein:
each of X
1
and X
3
independently represents Arg or Lys, each of X
2
, X
4
and X
6
independently represents Ile or Leu, and X
7
represents Phe, Tyr or Trp;
and a salt thereof.
As still another embodiment, the present invention provides a peptide represented by the amino acid sequence formula (E):
H-X
1
-X
2
-X
3
-X
4
-Gly-X
6
-X
7
-Asp-Gln-Leu-Ser-Lys-NH
2
(E) (SEQ ID NO:5)
wherein:
each of X
1
and X
3
independently represents Arg or Lys, each of X
2
, X
4
and X
6
independently represents Ile or Leu, and X
7
represents Phe, Tyr or Trp;
and a salt thereof.
As still another embodiment, the present invention provides a peptide represented by the amino acid sequence formula (F):
H-X
1
-X
2
-X
3
-X
4
-Gly-X
6
-X
7
-Asp-Gln-Leu-Ser-Arg-NH
2
(F) (SEQ ID NO:6)
wherein:
each of X
1
and X
3
independently represents Arg or Lys, each of X
2
, X
4
and X
6
independently represents Ile or Leu, and X
7
represents Phe, Tyr or Trp;
and a salt thereof.
As still another embodiment, the present invention provides a peptide represented by the amino acid sequence formula (G):
H-X
1
-X
2
-X
3
-X
4
-Gly-X
6
-X
7
-Asp-Gln-Leu-Ser-Lys-Leu-NH
2
(G) (SEQ ID NO:7)
wherein:
each of X
1
and X
3
independently represents Arg or Lys, each of X
2
, X
4
and X
6
independently represents Ile or Leu, and X
7
represents Phe, Tyr or Trp;
and a salt thereof.
As still a further embodiment, the present invention provides a peptide represented by the amino acid sequence formula (H):
H-X
1
-X
2
-X
3
-X
4
-Gly-X
6
-X
7
-Asp-Gln-Leu-Ser-Arg-Leu-NH
2
(H) (SEQ ID NO:8)
wherein:
each of X
1
and X
3
independently represents Arg or Lys, each of X
2
, X
4
and X
6
independently represents Ile or Leu, and X
7
represents Phe, Tyr or Trp;
and a salt thereof.
Among the above peptides provided by the present invention, the most preferred embodiment is a peptide represented by the amino acid sequence formula (1):
H-Arg-Ile-Lys-Ile-Gly-Leu-Phe-Asp-Gln-Leu-Ser-Lys-Leu-NH
2
(1) (SEQ ID NO:1)
and a salt thereof, or a peptide represented by the amino acid sequence formula (97):
H-Arg-Ile-Lys-Ile-Gly-Leu-Phe-Asp-Gln-Leu-Ser-Arg-Leu-NH
2
(97) (SEQ ID NO:2)
and a salt thereof.
As another embodiment, the present invention provides a pharmaceutical composition containing the peptide represented by the amino acid sequence formula (A) or a salt thereof for treatment of glutamate receptor related diseases.
As still another embodiment, the present invention provides use of the peptide represented by the amino acid sequence formula (A) or a salt thereof for treatment of glutamate receptor related diseases.
As still a further embodiment, the present invention provides a method for treatment of glutamate receptor related diseases which composing administering an effective amount of the peptide represented by the amino acid sequence formula (A) or a salt thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
In the present specification and in each of the above formulae, Gly stands for a glycine residue, Asp stands for an aspartic acid residue, Gln stands for a glutamine residue, Arg stands for an arginine residue, Lys stands for a lysine residue, Ile stands f
Itagaki Yasuhiro
Kawai Nobufumi
Konno Katsuhiro
Takayama Hiroaki
Crowell & Moring LLP
Kam Chih-Mim
Low Christopher S. F.
Suntory Limited
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