JPH08231592A - New peptide and its use - Google Patents

Abstract

PURPOSE: To obtain a new peptide having a tyrosinase activity inhibiting action and suitable for the application to the use requiring the inhibiting action. CONSTITUTION: This peptide or its salt has the amino acid sequence shown by the following general formula. Ala-Val-Thr-Asp-Asn-Glu-Ile-Val-Pro-Gln-Cys- Leu-Ala-Asn-Gly-Ser-Lys-Cys-Tyr-Ser-His-Asp-Val-Cys-Cys-Thr-Lys-Arg-Cy s-His- Asn-X-Ala-Lys-Lys-Cys-Val-Thr (X is DOPA or Tyr). As an alternative, a peptide or its salt obtained by removing 10 amino acids from the N-terminal of the above peptide and deficient in one or more constituent amino acids is used. These peptides or their salts are useful as tyrosinase activity inhibiting agents.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel physiologically active peptide and its use, and more particularly to a novel peptide having an inhibitory action on tyrosinase activity and its use.

[0002]

BACKGROUND OF THE INVENTION Tyrosinase is an enzyme that catalyzes the formation of melanin pigment and is widely present in the natural world, and those having an action of suppressing the tyrosinase activity are known for various industrial uses. For example, Japanese Patent Publication 61-10447
As disclosed in, for example, Japanese Patent Publication, tyrosinase activity inhibitors are used as a whitening agent for the prevention and treatment of melanin production from a cosmetic point of view. Further, in fruits, seeds and grains of plants, as disclosed in, for example, JP-A-62-198372, browning occurs due to the production of melanin by tyrosinase. It is used.
For shellfish such as shrimp and crab, for example, JP-A-1-25
As disclosed in Japanese Patent No. 7427 and the like, it is used as a freshness-retaining agent in order to suppress the activity of tyrosinase and maintain the freshness. In the case of pests, for example, Japanese Patent Laid-Open No. 1-1
As disclosed in Japanese Patent No. 32502 and the like, it is used as a pest control agent by suppressing melanin production.

However, the tyrosinase activity inhibitors used for these purposes are not sufficiently satisfactory in terms of their tyrosinase activity inhibitory effect, and they are stable to pH and temperature usually used and have tyrosinase activity. A higher inhibitory effect was desired.

[0004]

From this point of view,
A search for inhibitors of tyrosinase present in animals, especially insects, found that a specific peptide had a very high tyrosinase activity inhibitory effect and was stable to commonly used pH and temperature. The present invention has been completed.

[0005]

The present invention has a very high tyrosinase activity inhibitory effect, and is a commonly used p
Novel peptides that are stable to H and temperature,
It provides its useful use. That is, according to the present invention, there is provided a tyrosinase activity inhibitor characterized by comprising a peptide having an amino acid sequence represented by the following general formula or a salt thereof and an active ingredient thereof. Ala-Val-Thr-Asp-Asn-Glu-Ile-Val-Pro-Gln-Cys-Leu-Al
a-Asn-Gly-Ser-Lys-Cys-Tyr-Ser-His-Asp-Val-Cys-Cys-
Thr-Lys-Arg-Cys-His-Asn-X-Ala-Lys-Lys-Cys-Val-Thr
(In the formula, X represents DOPA or Tyr.) When amino acids, peptides, etc. are represented by symbols in the present invention, the usual symbols defined by IUPAC and IUP or used in the field of peptide chemistry are used. .

Examples of symbols are as follows. Ala ・ ・ ・ Alanine Ile ・ ・ ・ Isoleucine Arg ・ ・ ・ Arginine Leu ・ ・ ・ Leucine Asn ・ ・ ・ Asparagine Lys ・ ・ ・ Lysine Asp ・ ・ ・ Aspartic acid Pro ・ ・ ・ Proline Cys ・ ・ ・ Cysteine Ser ・ ・ ・Serine Gln ・ ・ ・ Glutamine Thr ・ ・ ・ Threonine Glu ・ ・ ・ Glutamic acid Tyr ・ ・ ・ Tyrosine Gly ・ ・ ・ Glycine Val ・ ・ ・ Valin His ・ ・ ・ Histidine DOPA ・ ・ ・ 3,4-Dihydroxy phenylalanine The peptide of the invention may be a peptide in which at least one amino acid is deleted from the N-terminal of the peptide of the present invention, as long as the peptide does not lose the tyrosinase activity inhibitory effect.

[0007]

[Detailed Description of the Invention]

<Peptide Production Method> The peptide of the present invention can be produced by a method such as an extraction method from a living body, a synthesis method, and a gene recombination method, and any of them can be used. As an extraction method from living organisms, various purification methods are combined and extracted from insects, especially flies. Further, the peptide of the present invention is a low molecular weight peptide in which at least one or more amino acids are deleted from the peptide obtained by removing 10 amino acids from the N-terminal of the peptide of the present invention, as long as it does not lose the tyrosinase activity inhibitory effect. But it's okay. The low molecular weight peptide can be produced by the chemical cleavage method or the cleavage method using an enzyme such as proteolytic enzyme and the chemical synthesis of the peptide shown below, and any of the methods can produce the low molecular weight peptide. it can.

The chemical cleavage method includes, for example, cleavage of the binding moiety of aspartic acid, histidine and the like by using dilute acid or aqueous ammonia under limited conditions, and cleavage of the asparagine-glycine bond by using hydroxylamine. A method is used. Examples of the method for cleaving the peptide using an enzyme include, for example, cleavage of a lysine-binding portion by lysyl endopeptidase, etc., cleavage of an arginine-binding portion by arginyl endopeptidase, etc., and limitation by an enzyme using a protease such as papain or trypsin. A method such as a decomposition method is used.

As a method for chemically synthesizing peptides, the Boc method for protecting α-amino groups and side chain functional groups of amino acids with benzyl alcohol-based protecting groups and the Fmoc method for protecting with t-butyl alcohol-based protecting groups are used. A liquid phase method, a solid phase method, and a method combining the solid phase method and the liquid phase method are used. As these low molecular weight peptides, those purified by various purification methods can be used, but unpurified peptides can be used as long as they have a tyrosinase activity inhibitory effect.

<Uses of Peptide> The tyrosinase activity-inhibitory effect of the peptide thus obtained was examined. As a result, it was found that the peptide of the present invention has a tyrosinase activity-inhibitory effect and is used for various purposes. Although the form of tyrosinase activity inhibition is different, it has the same stable and excellent tyrosinase activity inhibitory effect as kojic acid, so it has an inhibitory effect on tyrosinase activity of drugs, quasi drugs, cosmetics, foods and pest control agents. It has been found that it can be used for various applications in which is required.

As a drug, for example, a therapeutic agent for pigmentation that develops in the dermis portion of the skin such as spots, senile lentigines, endogenous melasma, and nevus, exerts an excellent tyrosinase activity inhibitory action. For quasi-drugs and cosmetics,
For example, it is useful as a whitening agent.

[0012] As foods, due to their tyrosinase activity inhibitory action, they can be used for various purposes such as agents for preventing browning of crustaceans and fish and freshness-retaining agents for fresh foods and vegetables.

Examples of the pest control agent include various pests, for example, Hemiptera pests such as leafhoppers such as leafhoppers, Spodoptera litura,
Examples thereof include use as a pesticide against lepidopteran pests such as diamondback moth and other pests of the order Coleoptera, pests of the order Diptera, pests of the cockroaches, pests of the arachnid, pests of the mites and the like.

<Uses as Pharmaceuticals, Quasi-drugs and Cosmetics> The dosage forms of pharmaceuticals, quasi-drugs and cosmetics containing the peptide of the present invention as an active ingredient can be used in various forms such as cream, which can be applied externally. Ointments, emulsions, injections, liniments, poultices, plasters, eye drops,
Paste, lotion, emulsion, essence, pack,
Gel, lipstick, foundation, hair shampoo,
In addition to known forms such as hair rinse and hair tonic, various solid or liquid forms that can be orally administered, such as capsules, tablets, granules, powders, syrups, and drinks, etc. It can be freely used, and its base material can be widely used in any liquid and solid raw materials which are acceptable for skin and hair application or oral administration.

As the active ingredient, known active ingredients other than the peptide of the present invention, for example, ascorbic acid, hydroquinone, liquiritin and their derivatives used as whitening agents, kojic acid and kojic acid derivatives, and branching vasodilators Used as cepharanthin, vitamin E, vitamin E nicotinate, nicotinic acid, nicotinic acid amide, benzyl nicotinate, ginger tincture, capsicum tincture, used as a cooling agent camphor, menthol, used as an antibacterial agent Hinokitiol, benzalkonium chloride, undecylenic acid, lysozyme chloride, which is used as an anti-inflammatory agent, glycyrrhizin, allantoin, licorice extract, senburi extract, garlic extract, carrot extract, sardine extract, which are extracts derived from animals and plants. Rosemary extract, aloe extract, placental extract, one selected from such liver extracts or two or more properly selected may be used in combination freely.

At this time, various known additives such as antiseptics, fragrances, stabilizers, colorants, ultraviolet absorbers, antioxidants, moisturizers, thickeners and the like can be added if necessary. The compounding amount of the peptide which is the active ingredient of the present invention may be appropriately changed depending on the application site, the degree of symptoms, the dosage form and the like, but is usually about 0.0001 to 10.00% by weight, preferably 0.01 to 5. About 00% by weight is added to the formulation. The peptide to be blended may be a purified one, but the extract or reaction solution may be used as it is.

<Use as whitening food> The peptide of the present invention is used as a whitening food in various forms such as jelly, drink, jam, biscuits, candy, and chocolate, which are commonly used for eating and drinking. It can be used in a known form.

<Use as a browning inhibitor and a freshness-retaining agent>
When used as an anti-browning agent or a freshness-retaining agent,
This peptide can be used by a known method for agricultural products, marine products, feeds, and the like. At that time, other known tyrosinase inhibitors that can be used as foods as required, such as ascorbic acid and other kojic acid, preservatives, perfumes, stabilizers, colorants, emulsifiers, antioxidants, seasonings, Various known additives such as thickeners such as alcohol, protamine, red No. 2, yellow No. 4, BHA, carrageenan, natural flavor, β-carotene monoglyceride, sodium glutamate, sorbitol, stevia, fructose, citric acid, etc. It can also be added.

The amount of the peptide of the present invention to be blended may be appropriately changed depending on the form of the food and the like, but usually about 0.0001 to 10.00% by weight, preferably about 0.05 to 5.00% by weight in the food. It is good to mix in. The peptide of the present invention to be blended may be a purified one, but the extract or reaction solution may be used as it is.

<Use as a pest control agent> When the peptide of the present invention is used as a pest control agent, various known forms such as paste, solution and powder can be used. At that time, other known pesticides, bactericides, fragrances, stabilizers, coloring agents, antioxidants, extenders, thickeners, and various other known additives such as kojic acid, if necessary.
Parathion, diflubenzourone, sodium dodecylbenzenesulfonate, dimethylformamide, methanol, ethanol, isopropyl alcohol, polyoxyethylene nonylphenyl ether, kaolin, silicic acid and the like can also be added.

The amount of the peptide of the present invention to be blended may be appropriately changed depending on the form of the anthelmintic agent and the like, but usually about 0.0001 to 20.00% by weight, preferably 0.01 to 1
It is advisable to add about 0.00% by weight to the pest control agent.
The peptide to be blended may be a purified one,
The extract or reaction solution may be used as it is. Next, a method for producing a peptide which is an active ingredient of the present invention, a drug, a quasi drug, a cosmetic, a food and other examples and test examples of the effect thereof are shown, but these do not limit the present invention at all. Absent.

<Production Example of Peptide> As a production example of the novel peptide of the present invention, an extraction method from housefly will be shown.
This peptide was prepared by preparing a crude extract from housefly, fractionation using SP-Toyopearl 550C column, Sephadex G-25.
Column fractionation and HPLC of YMC-Pack Protein-RP
Of fractions using column and YMC-Pack C8-A203 column
Purified in stages. The tyrosinase activity inhibitory effect of the tyrosinase activity inhibitory fraction was measured using the following method.
That is, using tyrosinase prepared from flies as an enzyme solution, adding DOPA at a final concentration of 2 mM and each fraction,
The tyrosinase activity inhibitory effect was determined by adding 50 mM phosphate buffer to a total volume of 3 ml and incubating at 25 ° C. and following the absorbance at 470 nm. The protein amount of each fraction was determined by the method of Lowry et al. (Journal of the Biological Chemistry, 19
Vol. 3, pp. 265-275, 1951).

(1) Preparation of crude extract from housefly: To 1.5 kg of the housefly pupae, 6 L of 0.1 M acetate buffer solution (pH 4.0) was added and homogenized at 4 ° C. The homogenate solution was filtered through gauze, the filtrate was heated at 70 ° C. for 30 minutes, and centrifuged to obtain a clear supernatant solution. Solid ammonium sulfate was added to the supernatant so that the concentration became 60%, and the mixture was centrifuged. Further, solid ammonium sulfate was added to the supernatant so that the concentration became 80%, and the mixture was centrifuged. The precipitate was dialyzed against water. The dialyzed solution was centrifuged to obtain a clear supernatant as a crude extract.

(2) SP-Toyopearl 550C column
Fractions used This crude extract was equilibrated with 50 mM phosphate buffer S
P-Toyopearl 550C was added to a 440 ml column and the sodium chloride concentration was changed from 0M to 0.6M.
The fraction inhibiting tyrosinase activity was eluted. The fraction inhibiting tyrosinase activity was eluted at a sodium chloride concentration of around 0.3M. The elution chromatogram is shown in FIG.

(3) Sephadex G-25 column Tyrosinase inhibitory activity fraction was lyophilized and dissolved in water. The solution was applied to a Sephadex G-25 column (diameter 2.8 cm x length 1) equilibrated with 50 mM phosphate buffer.
10 cm) to elute the tyrosinase activity inhibition fraction. Fractions that inhibit tyrosinase activity from 250 ml to 4
It was detected in the eluate of 00 ml, and the fractions were collected, dialyzed and freeze-dried, and the dried product was dissolved in water.

(4) YMC-Pack Protein-RP HPLC
Fractionation using ram The fractions collected on Sephadex G-25 column were collected using YMC-Pack.
It was purified using a Protein-RP HPLC column (diameter 4.6 mm × length 150 mm). That is, fractionation was performed with a gradient of 0% to 55% acetonitrile containing 0.1% trifluoroacetic acid at a flow rate of 1 ml / min. The detection wavelength was two wavelengths of 280 nm and 214 nm. The elution chromatogram is shown in FIG. The retention time of the tyrosinase activity inhibitory fraction (dotted line in FIG. 2) was about 28 minutes.
The fractions thus fractionated were lyophilized, redissolved in 100 μl of water and used for analysis. The active fraction was prepared under the same conditions as above, using a Wakosil 5C ₄ -200 column (diameter 4.6 mm x length 2
50 mm) and rechromatographed twice.

(5) Using YMC-Pack C8-A203 column
Image Wakosil 5C ₄ The collected fractions -200 column YMC-Pack C8-A2
It was purified using 03 column (diameter 4.6 mm x length 250 mm). That is, 1 containing 0.1% trifluoroacetic acid
Fractionation was performed with a gradient of 2% to 30% acetonitrile at a flow rate of 0.2% acetonitrile / min. Two kinds of substances having a retention time of about 55 minutes (peptide-a) and a retention time of about 56 minutes (peptide-b) were obtained as fractions showing tyrosinase inhibitory activity.

<Analysis Result> The analysis result of the peptide of the present invention thus obtained is shown below. (1) Measurement of amino acid sequence The amino acid sequence of the peptide of the present invention was measured using an Edman degradation automatic analyzer. The peptide of the present invention is
The following two amino acid sequences are shown: peptide-a where X is DOPA and peptide-b where X is Tyr. Ala-Va
l-Thr-Asp-Asn-Glu-Ile-Val-Pro-Gln-Cys-Leu-Ala-Asn-
Gly-Ser-Lys-Cys-Tyr-Ser-His-Asp-Val-Cys-Cys-Thr-Ly
s-Arg-Cys-His-Asn-X-Ala-Lys-Lys-Cys-Val-Thr (In the formula, X represents DOPA or Tyr.)

(2) Stability Both the peptides of the present invention, peptide-a and peptide-b, had a tyrosinase activity inhibitory effect at 40 ° C. for 30 days. The peptide of the present invention was stable under the temperature conditions during normal use.

(3) pH stability The tyrosinase activity inhibitory effect of the peptides of the present invention, peptide-a and peptide-b, was stable at pH 4 to 10. The peptide of the present invention has a normal pH
It was stable under the conditions.

<Example> The peptides of the present invention, peptide-a and peptide-b, and both peptides were cleaved at the 10th position from the N-terminus, Gln and Cys, using a protease, and the 11th Cys to C were cleaved. Peptides of 28 amino acids up to the terminal Thr (Peptide-a and Peptide-b
The results of the tyrosinase activity inhibition test are shown for each sample of peptide-a1 and peptide-b1).

<Test Example> Using tyrosinase prepared from flies as an enzyme solution, the final concentration is 1.25 mM to 5.0.
mMPA of PAPA and the peptide of 1.5 nM to 6.
0 nM was added, 50 mM phosphate buffer was added so that the total amount was 3 ml, and the mixture was incubated at 25 ° C., and the absorbance at 470 nm of the produced dopachrome was traced. Using the initial production rate of dopachrome, Lineweaver-Burk
The plot was performed and the type of tyrosinase activity inhibition and the inhibition constant were calculated. The results are shown in Table 1. As is clear from this result, the tyrosinase inhibitory activities of the peptide of the present invention and the low-molecular-weight peptide were both comparable and extremely high.

[0033]

<Prescription Example> Next, a more specific example of the useful application of the present invention will be shown by a prescription example. In the prescription example, "appropriate amount" means
It means a blending amount of 100% by weight as a whole.

<Formulation Example 1> Cream (% by weight) A Monostearic acid 2.0 Polyethylene glycol (40.E.0) Self-emulsifying glyceryl monostearate 5.0 Stearic acid 5.0 Behenyl alcohol 1.0 Liquid paraffin 10.0 Glyceryl trioctanoate 10.0 B Glycerin 5.0 Ethylparaben 0.1 Peptide-a 1.0 Purified water Appropriate amount A component belonging to A is dissolved by heating. Separately, the components belonging to B are dissolved by heating. B was added to A, and the mixture was stirred, emulsified, and cooled to produce a cream.

<Formulation Example 2> Emulsion (wt%) Peptide-b 0.2 A Monostearate polyoxyethylene sorbitan (20.E.0) 1.0 Monostearate polyoxyethylene sorbit (60.E.0) ) 0.5 Lipophilic glyceryl monostearate 1.0 Stearic acid 0.5 Behenyl alcohol 0.5 Avocado oil 4.0 Glycel trioctanoate 4.0 B 1,3-butylene glycol 5.0 Methylparaben 0.2 Purified water A proper amount of the ingredients belonging to A are dissolved by heating. Separately, the components belonging to B are dissolved by heating. B was added to A, a peptide as an active ingredient was added, and the mixture was stirred, emulsified, and cooled to prepare an emulsion.

<Formulation Example 3> Lotion (% by weight) Peptide-a 0.5 Allantoin 0.1 Polyoxyethylene hydrogenated castor oil (60.E.0) 8.0 Ethanol 15.0 Ethylparaben 0.1 Quen Acid 0.1 Sodium citrate 0.3 1,3 Butylene glycol 4.0 Disodium edetate 0.01 Purified water Appropriate amount The above components were mixed, uniformly stirred and dissolved to produce a lotion.

<Formulation Example 4> Cream pack (% by weight) Peptide-b 0.05 A Veam 5.0 Squalane 2.0 Propylene glycol 5.0 Vitamin B ₁₂ 0.05 Purified water Appropriate amount B Zinc oxide 10.0 C Ethanol 5.0 Mix components belonging to A, swell by stirring, and add B little by little. C was gradually added to this, and the peptide of the present invention was further added and kneaded until a paste was formed to prepare a cream pack.

<Formulation Example 5> Essence (wt%) Peptide-a 0.2 1% Carboxyvinyl polymer solution 10.0 Glycerin 20.0 Hyaluronic acid 0.5 Ethanol 1.0 Purified water Appropriate amount The essence was manufactured by mixing, stirring and dissolving uniformly.

<Formulation Example 6> Hydrophilic ointment (% by weight) Peptide-b 0.1 Ascorbic acid 0.5 A Polyoxyethylene cetyl ether 2.0 Glyceryl monostearate 10.0 Liquid paraffin 10.0 Vaseline 4. 0 Cetanol 5.0 B Propylene glycol 10.0 Methylparaben 0.1 Purified water Appropriate amount The components belonging to A are dissolved by heating. Separately, the components belonging to B are dissolved by heating. After adding B to A, the peptide of the present invention which is an active ingredient, ascorbic acid, and stirring and emulsifying,
Cooled to produce a hydrophilic ointment.

<Formulation Example 7> Aerosol agent (% by weight) A peptide-a 5.0 benzyl nicotinate 0.01 vitamin E acetate 0.05 cetanol 1.2 propylene glycol 4.0 ethanol 8.0 purified water suitable amount B Freon 123 / 141b (57:43) 7.0 The components belonging to A were uniformly mixed and dissolved, placed in an aerosol container, and B was filled in the container by an ordinary method to produce an aerosol agent.

<Formulation Example 8> Pap agent (% by weight) Peptide-b 10.0 A Polyacrylic acid 30.0 Sorbitan monooleate 1.0 Purified water 30.7 B Sodium polyacrylate 7.0 Aluminum chloride 0 .3 concentrated glycerin 20.0 titanium oxide 1.0 A component belonging to A is dissolved by heating. Separately, the components belonging to B are dissolved by heating. The peptide of the present invention, which is the active ingredient, was added to the mixture of A and B, and the mixture was stirred and mixed to produce a poultice.

<Formulation Example 9> Tablet confectionery (% by weight) Citric acid 1.0 Skim milk powder 15.0 Sucrose fatty acid ester 1.0 Flavor 0.8 Peptide-a 0.1 Kojic acid 0.05 Granulated sugar 20. 0 Lactose 62.05 The above raw materials were uniformly mixed, granulated, and tableted to produce.

<Formulation Example 10> Candy (% by weight) A powdered Marvit 83.0 citric acid 0.4 water 15.549 B flavor 1.0 yellow No. 4 0.001 peptide-b 0.05 A mixed solution Concentrate by heating in a vacuum pan under reduced pressure to a water content of 2 to 5%, transfer to a cooling plate, add B in sequence and cool to about 60 ° C, and use a roller or stamping machine. Molded and manufactured.

<Formulation Example 11> Wettable powder (pest control agent) (% by weight) Peptide-a 0.01 Silicic anhydride 5.0 Sodium dodecylbenzenesulfonate 2.0 Kaolin Appropriate amount The above components are mixed and mixed with a mixer. To produce a wettable powder.

<Formulation Example 12> Emulsion (pest control agent) (% by weight) Peptide-b 1.0 Dimethylformamide 40.0 Methanol 29.0 Ethanol 10.0 Isopropyl alcohol 10.0 Polyoxyethylene nonylphenyl ether 10. 0 The above components were uniformly mixed and dissolved to prepare an emulsion.

[0047]

Since the novel peptide of the present invention has a high tyrosinase activity inhibitory effect, it is required to have a tyrosinase activity inhibitory effect for drugs, quasi drugs, cosmetics, foods and pest control agents. It can be used for various purposes.

[Brief description of drawings]

FIG. 1 is an elution chromatogram of a tyrosinase activity-inhibiting fraction eluted from a housefly crude extract using an SP-Toyopearl 550C column.

FIG. 2 H of YMC-Pack Protein-RP
It is an elution chromatogram of the tyrosinase activity inhibition fraction by a PLC column.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 38/55 C12N 9/99 C12N 9/99 A01N 37/46 // A01N 37/46 A61K 37 / 64

Claims (3)

[Claims] 1. A peptide having the amino acid sequence represented by the following general formula or a salt thereof. Ala-Val-Thr-Asp-Asn-Glu-Ile-Val-Pro-Gln-Cys-Leu-Al
a-Asn-Gly-Ser-Lys-Cys-Tyr-Ser-His-Asp-Val-Cys-Cys-
Thr-Lys-Arg-Cys-His-Asn-X-Ala-Lys-Lys-Cys-Val-Thr
(In the formula, X represents DOPA or Tyr.) 2. From the N-terminal of the peptide according to claim 1, 10
A peptide in which one or more constituent amino acids are deleted from the peptide in which one amino acid is removed, or a salt thereof. 3. A tyrosinase activity inhibitor comprising the peptide according to claim 1 or 2 or a salt thereof as an active ingredient.