Pentapeptide with specific conformation, its production and use

Details Pentapeptide with specific conformation, its production and use Pentapeptide with specific conformation, its production and use

2001-11-15

2003-08-26

Celsa, Bennett M (Department: 1639)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S009100, C530S333000, C530S335000, C530S338000

Reexamination Certificate

active

06610655

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel method for producing a cyclic pentapeptide having a &bgr;-turn and a &ggr;-turn, cyclic pentapetides having a &bgr;-turn and a &ggr;-turn and use thereof.
PRIOR ART
The &bgr;-turn and the &ggr;-turn are known as one of regular structures of proteins or peptide molecules, and have structures bending at 4- and 3-amino acid residues, respectively. Usually, the &bgr;-turn forms a hydrogen bond between carbonyl oxygen in the i-position and an amide proton in the i+3-position, and is classified into type I and type II according to two dihedral angles &phgr; and &psgr; of the i+1-position and the i+2-position. The &ggr;-turn forms a hydrogen bond between the i-position and the i+2-position. Such turn structures relates to intermolecular recognition and molecular interaction in many cases, because of their projected structures from molecular surfaces. With recent developments of X-ray crystal structure analysis and NMR analysis, three-dimensional structures of many biologically active peptides have been determined. Examples of peptides containing &bgr;-turns in active sites include enkephalin [T. S. Sudha & P. Balaram,
Int. J. Pept. Protein Res.,
21(4), 381-388 (1983), and M. Goodman et al.,
Biopolymers,
26 (Supp.), S25-S32 (1987)] and somatostatin [U. Nagai et al.,
Pept.: Chem. Biol., Proc. Am. Pept. Symp.
10th, 129-130 (1988)]. Attempts have further been made to imitate the &bgr;-turn portions with non-peptide compounds [J. B. Ball & P. F. Alewood,
J. Mol. Recognit.,
3(2 , 55-64 (1990), and G. L. Olson et al.,
J. Am. Chem. Soc.,
112(1), 323-333 (1990)]. It has also been reported that RGD(Arg-Gly-Asp)-related peptides having vitronectin-sensitive cell adhesion activity have &ggr;-turns in adhesion sites [G. Muler et al.,
Angew. Chem. Int. Ed. Engl.,
31(3), 326-328 (1992)]. Recently, cyclic pentapeptide BQ123 was reported as an antagonist against endothelin by Banyu Pharmaceutical Co., Ltd. (U.S. Pat. No. 5,114,918) but it does not describe its conformation. Further, a specific cyclic pentapeptide as an endothelin receptor-antagonist or as an endothelin-antagonist, respectively has been reported to have a &bgr;-turn and a &ggr;-turn [R. A. Atkinson & J. T. Pelton,
FEBS Lett.,
296(1), 1-6 (1992), and S. R. Krystek Jr. et al., FEBS Lett., 299(3), 255-261 (1992)]. This is considered to be a three-dimensional structure inherent in the specific amino acid sequence of that specific cyclic pentapeptide.
SUMMARY OF THE INVENTION
A method for synthesizing peptides having a &bgr;-turn followed by a &ggr;-turn or a &ggr;-turn followed by a &bgr;-turn, can contribute to the development of drugs. Further, methods for introducing desired amino acid residues into the sites for the &bgr;- and &ggr;-turns can facilitate effective designing of compounds having biological activity.
The present inventors synthesized various cyclic pentapeptides and conducted intensive investigations of the conformations thereof. As a result, the present inventors discovered a novel manufacturing method by which compounds having &bgr;- and &ggr;-turns could be synthesized at will, regardless of residues.
The present invention directs to a novel method for forming &bgr;- and &ggr;-turns, only by controlling optical activity of a main chain of a cyclic pentapeptide, regardless of the kind of residues, a cyclic pentapeptide having &bgr;- and &ggr;-turns and use thereof.
Namely, the present invention provides (1) A cyclic pentapeptide having a &ggr;-turn and a &bgr;-turn wherein the cyclic pentapeptide has the following formula (I):
Cyclo(-A
1
-A
2
-A
3
-A
4
-A
5
-)  (I)
wherein A
1
, A
2
, A
3
, A
4
and A
5
are amino acid residues;
said pentapeptide comprising amino acid residues in positions 1-2-3 to form a &ggr;-turn, and amino acid residues in positions 3-4-5-1 to form a &bgr;-turn in combination with the &ggr;-turn;
in which D-&agr;-amino acid residues are selected for A
1
, A
3
and A
5
and L-&agr;-amino acid residues are selected for A
2
and A
4
or L-&agr;-amino acid residues are selected for A
1
, A
3
and A
5
and D-&agr;-amino acid residues are selected for A
2
and A
4
;
(2) the cyclic pentapeptide of (1), in which A
1
, A
3
and A
5
are D-&agr;-amino acid residues, and A
2
and A
4
are L-&agr;-amino acid residues, with the proviso that when A
1
is D-Asp, A
3
is D-Val, A
4
is L-Leu and A
5
is D-Trp, A
2
is L-amino acid other than L-Pro; (3) the cyclic pentapeptide of (2), in which A
1
is D-alanine, D-valine, D-norvaline, D-leucine, D-norleucine, D-isoleucine, D-alloisoleucine, D-phenylalanine, D-tyrosine, D-tryptophan, D-serine, D-threonine, D-ornithine, D-lysine, D-arginine, D-histidine or D-methionine; A
2
is an L-&agr;-amino acid; A
3
is a D-&agr;-amino acid; A
4
is an L-&agr;-amino acid; and A
5
is D-&agr;-amino acid; (4) the cyclic pentapeptide of (2), in which A
1
is D-aspartic acid, D-glutamic acid or D-cysteic acid; A
2
is an L-&agr;-amino acid; A
3
is a D-&agr;-amino acid; A
4
is an L-&agr;-amino acid; and A
5
is D-valine, D-norvaline, D-leucine, D-norleucine, D-isoleucine, D-alloisoleucine, D-serine, D-threonine, D-aspartic acid, D-glutamic acid, D-ornithine, D-lysine, D-arginine, D-histidine, D-methionine or D-cysteine; (5) the cyclic pentapeptide of (2), in which A
1
is D-aspartic acid, D-glutamic acid or D-cysteic acid; A
2
is an L-&agr;-amino acid; A
3
is D-phenylalanine, D-tyrosine, D-tryptophan, D-serine, D-aspartic acid, D-glutamic acid, D-ornithine, D-lysine, D-arginine, D-histidine, D-methionine or D-cysteine; A
4
is an L-&agr;-amino acid; and A
5
is D-phenylalanine, D-tyrosine, D-alanine or D-tryptophan; (6) the cyclic pentapeptide of (1), in which A
1
, A
3
and A
5
are L-&agr;-amino acid residues, and A
2
and A
4
are D-&agr;-amino acid residues; (7) the cyclic pentapeptide of (1), in which A
1
is a D-&agr;-amino acid; A
2
is an L-&agr;-amino acid having a protective group for the amino acid; A
3
is a D-&agr;-amino acid; A
4
is an L-&agr;-amino acid; and A
5
is a D-&agr;-amino acid; (8) the cyclic pentapeptide of (7), in which a protective group is hydrophobic; (9) the cyclic pentapeptide of (8), in which a protective group is benzyl; (10) the cyclic pentapeptide of (7) is cyclo(-D-Glu-Ser(Bzl)-D-Leu-Leu-D-Trp); (11) the cyclic pentapeptide of (7) is cyclo(-D-Glu-Thr(Bzl)-D-Leu-Leu-D-Trp); (12) an NK2 receptor antagonist composition comprising any one of the cyclic pentapeptides of (1) to (11) and pharmaceutically acceptable carrier; (13) the composition of (12), in which said antagonist is an antiasthmatic agent, an anti-inflammatory agent or an antarthritic agent; (14) a method for producing a cyclic pentapeptide having a &ggr;-turn and a &bgr;-turn wherein the cyclic pentapeptide has the following formula (I):
Cyclo(-A
1
-A
2
-A
3
-A
4
-A
5
-)  (I)
wherein A
1
, A
2
, A
3
, A
4
and A
5
are amino acid residues;
said method comprising selecting and reacting amino acid residues in positions 1-2-3 to form a &ggr;-turn, and selecting and reacting amino acid residues in positions 3-4-5-1 to form a &bgr;-turn in combination with the &ggr;-turn;
in which D-&agr;-amino acid residues are selected for A
1
, A
3
and A
5
and L-&agr;-amino acid residues are selected for A
2
and A
4
or L-&agr;-amino acid residues are selected for A
1
, A
3
and A
5
and D-&agr;-amino acid residues are selected for A
2
and A
4
; (15) the method of (14), further comprising condensing two kinds of fragments to form a linear pentapeptide, and then cyclizing resulting linear pentapeptide to form the cyclic pentapeptide; and (16) a method of treating mammalian asthma, inflammation or arthritis which comprises administering to said mammal a pharmaceutical composition comprising an effective amount of any one of the cyclic pentapeptides of claim 1 to 11.


REFERENCES:
patent: 6346604 (2002-02-01), Wakimasu et al.
Rudinger, J. Peptide Hormones (ed. J.A. Parsons: University Park Press Jun. 1976) pp. 1-6.*
Krystek et al., FE

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