JP2010001280A - New peptide and prolyl endopeptidase inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new peptide having prolyl endopeptidase inhibiting activity from a protease decomposition liquid of saury scale. <P>SOLUTION: Peptides comprising Ile-Gly-Phe-Pro-Leu-Pro, Ala-Ile-Leu-Pro-Pro, Ile-His-Val-Pro-Pro and Ile-Thr-Pro-Pro-Pro having prolyl endopeptidase inhibiting activity, developing antiamnestic effect in vivo and having extremely low toxicity are produced from saury scale by treating the scale with a protease, etc. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

The present invention relates to novel peptides and prolyl endopeptidase inhibitors.

The novel peptides have advantages as prolyl endopeptidase inhibitors and anti-amnesic agents.
JP 2003-267995 A JP 2003-306498 A JP 2005-206469 A JP 2006-199671 A JP 2006-199672 A Maruyama, S .; Et al .: Biosci. Biotech. Biochem. 60, 358-359 (1996). Kimura, K .; Et al .: Biosci. Biotech. Biochem. 61, 1754-1756 (1997). Yoshimoto, T .; Et al: Biochem. Biophys. Acta, 569, 184-189 (1979).

Senile dementia is broadly classified into two types: Alzheimer's disease, and cerebrovascular dementia is classified into cerebrovascular dementia caused by cerebral infarction, intracerebral hemorrhage, subarachnoid hemorrhage and the like. It has been reported that the activity of an enzyme called prolyl endopeptidase is increased in the brain of patients with amnesia and dementia. If this enzyme is weakened, it can be expected to prevent or treat forgetfulness or dementia [ Non-patent document 1] [Non-patent document 2]. On the other hand, the inventor has so far obtained a fish scale-derived heptapeptide Leu-Gly-Gly-Pro-Gly-Ala-Pro, Val-Gly-Gly obtained by enzymatic degradation of fish scales that have been treated as fishery processing waste. -Pro-Pro-Gly-Ala, Pro-Val-Val-Pro-Gly-Ala-Gly and Ile-Val-Gly-Pro-Ala-Gly-Pro were found to have angiotensin converting enzyme inhibitory ability [Patent Document 1], Similarly, we have found the ability to inhibit activated oxygen in fish scale-derived heptapeptide Leu-His-Gln-Pro-Val-Pro-Glu and octapeptide Val-Ser-Gln-Pro-Ile-Gln-Gln-Glu [Patent Reference 2]. Furthermore, the rib-derived hexapeptide Lys-Gly-Thr-Pro-Ala-Gln was found to be capable of inhibiting angiotensin converting enzyme [Patent Document 3], and similarly, the rib-derived hexapeptide Lys-Gly-Thr-Pro-Ala-Gln Have found an ability to inhibit activated oxygen [Patent Document 4], and an angiotensin converting enzyme inhibitory ability has been found in the rib-derived tripeptide Leu-Ala-Tyr [Patent Document 5]. However, the prolyl endopeptidase inhibitory action and the anti-amnesic effect by oral administration of collagen peptides derived from fish scales are still unclear, and there is no report that development as a pharmaceutical has been advanced.

As a result of diligent research to solve the above-mentioned problems, the present inventor has found that the novel peptide according to the present invention obtained from fish scale collagen has an anti-amnesic effect and has completed the present invention. It was. That is, a substance having a pharmacological action was searched from a fish scale-derived collagen peptide, and the novel fish scale-derived collagen peptide was found to have a strong prolyl endopeptidase inhibitory action. Then, we conducted intensive research to put this novel fish scale-derived collagen peptide into practical use, and as a result, this new fish scale-derived collagen peptide has an anti-amnesic effect and is a progenitor derived from natural products. The utility as a tolyl endopeptidase inhibitor was found. The present invention is based on such knowledge. Collagen peptide derived from fish scales according to the present invention has the following formula:
(1) Ile-Gly-Phe-Pro-Leu-Pro
(2) Ala-Ile-Leu-Pro-Pro
(3) Ile-His-Val-Pro-Pro
(4) Ile-Thr-Pro-Pro-Pro
Is a novel peptide represented by the amino acid sequence of L-form, and the property at room temperature is a white powder.

Examples of the novel peptide according to the present invention include a method of chemically synthesizing and a method of separating and purifying from a decomposition solution of a proteolytic enzyme of saury. In the case of chemically synthesizing these novel peptides according to the present invention, the C-terminal (carboxyl terminal side) of the peptide to a polymeric solid support by a normal peptide synthesis method such as a liquid phase method or a solid phase method. Therefore, it is preferable that the L-form amino acids corresponding to the amino acid residues are sequentially joined by peptide bonds. The synthetic peptide thus obtained is cleaved from the polymeric solid support using trifluoromethanesulfonic acid, hydrogen fluoride, etc., and then the amino acid side chain protecting group is removed, and the reverse phase system is removed. It can refine | purify by the normal method using the column of.

As described above, the novel peptide according to the present invention can be separated and purified from the proteolytic enzyme digestion solution of saury Cololabis saira (mackerel pike) scale, in which case, for example, as follows. It can be carried out. Sanmauroko containing the above novel peptides is powdered and hydrolyzed. Hydrolysis is performed according to conventional methods. For example, when hydrolyzing with a proteolytic enzyme such as pepsin, after further hydrolyzing the saury, if necessary, the enzyme is adjusted to the optimum value, and the enzyme is added and incubated. Next, after neutralization as necessary, the enzyme is deactivated to obtain a hydrolyzed solution. The hydrolyzate is filtered using filter paper and / or celite to remove insoluble components, and the obtained filtrate is filtered using a semi-permeable membrane such as cellophane and a suitable solvent (for example, Tris-HCl buffer, Dialyze sufficiently in a neutral buffer solution of a phosphate buffer, etc., and a solution containing a component that has passed through a semipermeable membrane with a component in the filtrate is a strongly acidic cation exchange resin (for example, manufactured by Dow Chemical Co., Ltd.). Dowex 50W, etc.), a fraction containing a component having prolyl endopeptidase inhibitory activity is obtained from the adsorbed fraction, and the resulting prolyl endopeptidase inhibitory activity fraction is subjected to cation exchange gel filtration (for example, manufactured by Pharmacia) SP-Sephadex C-25 etc.), and the obtained activated oxygen inhibitory active fraction is further fractionated by reverse phase HPLC.

As the fish scale used in the method for producing a novel peptide according to the present invention, any fish scale may be used as long as the object of the present invention can be achieved, but preferably a sun scale. The novel peptide according to the present invention obtained as described above does not cause antibody production and does not cause anaphylactic shock when repeatedly administered intravenously. In addition, these peptides have a sequence structure of L-amino acids only, and are gradually degraded by in vivo protease after administration. Therefore, toxicity is extremely low and safety is very high (LD50> 5000 mg / kg: oral administration in rats). The novel peptide according to the present invention can be prepared into injections, tablets, capsules, granules, powders and the like using additives such as commonly used excipients. Examples of the administration method include injection into a mammal (eg, human, dog, rat, etc.) or oral administration. The dose is, for example, an amount of 0.01-10 mg peptide per kg animal body weight. The number of administration is usually about 1 to 4 times a day, but can be appropriately prepared depending on the administration route.

The types of excipients, binders, disintegrants, lubricants, etc. used in the above-mentioned various preparations are not particularly limited, and those used for ordinary injections, powders, granules, tablets or capsules are used. can do. Examples of additives used for tablets, capsules, granules, and powders include the following. Excipients include sugars such as crystalline cellulose, sugar alcohols such as mannitol, starches, anhydrous calcium phosphate, etc .; binders such as starches and hydroxypropylmethylcellulose; disintegrants such as carboxymethylcellulose and potassium salts thereof The lubricant may include stearic acid and its salts, talc, and waxes. Moreover, in preparation of a formulation, flavoring agents, such as menthol, a citric acid, its salts, and a fragrance | flavor, can be used as needed. A sterile composition for injection is prepared by dissolving or suspending the novel peptide according to the present invention in water for injection, physiological saline, sugar alcohol injection such as xylitol or mannitol, or glycol such as propylene glycol or polyethylene glycol by a conventional method. It can be made cloudy to make an injection. At this time, a buffer solution, a preservative, an antioxidant and the like can be added as necessary. The preparation containing the novel peptide according to the present invention is in the form of a freeze-dried product or a dry powder, and can be used by dissolving in a normal solubilizing agent such as water or physiological saline at the time of use.

The novel peptide according to the present invention has an excellent prolyl endopeptidase inhibitory action and exhibits an anti-amnesic effect and an anti-dementia effect. Therefore, since the progression of dementia symptoms of mild to moderate Alzheimer-type dementia and cerebrovascular dementia as a sequela of cerebral infarction can be delayed, it is useful as a preventive agent or symptom improving agent for amnesia.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention relates to peptides having a peptide structure having the following amino acid sequences having utility as pharmaceuticals and prolyl endopeptidase inhibitors containing these peptides as active ingredients.
(1) le-Gly-Phe-Pro-Leu-Pro
(2) Ala-Ile-Leu-Pro-Pro
(3) Ile-His-Val-Pro-Pro
(4) Ile-Thr-Pro-Pro-Pro
(In the formula, each symbol representing an amino acid residue is based on a conventional display method in amino acid chemistry)
EXAMPLES Examples and test examples will be described below as examples, and the present invention will be described in more detail. However, the present invention is not limited to these examples.

Production Example 1
After collecting Sanmauroko from the fishing port, foreign objects were removed by visual inspection. A 0.2% synthetic detergent for food (potassium polyphosphate, sucrose fatty acid ester) was added, and the mixture was stirred at 1,430 rpm (rpm) for 4 minutes. Thereafter, the product was thoroughly washed with water until the detergent disappeared, and then sodium hypochlorite was added for sterilization. After thoroughly washing with water until the bactericidal agent disappeared, it was dried at 80 ° C. for 40 minutes, and further dried at 70 ° C. for 100 minutes. After drying, the mixture was pulverized using a pulverizer jet mill to obtain San Mauroko powder. The general component analysis of the scale powder thus obtained was 7.8 g / 100 g water, 36 g / 100 g protein, 0.1 g / 100 g fat, and 56.1 g / 100 g ash. 5 L of 2N ammonia water was added to 500 g of Sanmauroko powder, and acetic acid extraction was performed at room temperature with slow stirring for 1 week. After stirring, Toyo Filter Paper No. The filter paper was filtered using 2 to obtain a filtrate. The filtrate was packed in a dialysis tube and dialyzed against running water for 2 days. The dialyzed internal solution was concentrated under reduced pressure and then lyophilized to obtain 20 g of protein powder derived from Sanmauroko powder. This was a recovery rate of 4% with respect to San Mauroko powder. After adding 500 mL of deionized water to 20 g of protein powder and adjusting the pH to 2.0, 0.6 g of pepsin was added to perform enzymatic degradation (37 ° C., 24 hours). After decomposition, the decomposition solution was packed in a dialysis tube and dialyzed against 6 L of deionized water for 2 days. The dialyzed external solution was concentrated under reduced pressure and then lyophilized to obtain 4.8 g of an enzyme-degraded extract powder. This was a recovery rate of 23.9% with respect to the protein powder. To 4.8 g of the enzyme-degraded extract powder, 100 mL of deionized water was added, followed by chromatography using a column (column size: 4.0 × 55 cm) packed with Dowex 50W × 4 (H ⁺ ). After washing with deionized water, the eluate was concentrated by elution with 2N aqueous ammonia. This concentrated solution was chromatographed using a column (column size; 2.6 × 133 cm) packed with Sephadex G-25. The chromatography conditions at that time were performed at a flow rate of 20 mL / h and each fraction of 3 mL. Fractions Nos. 24 to 35 were collected and concentrated as peptide fractions. Furthermore, this concentrate was chromatographed using a column (column size; 2 × 48.5 cm) packed with SP-Sephadex C-25 (H ⁺ ). Elution by concentration gradient method using 1 L of deionized water to 1 L of 3% saline was performed under the chromatography conditions of a flow rate of 60 mL / h and a fraction of 5 mL. SP-1 fraction (fraction numbers 31-45), SP-2 fraction (fraction numbers 46-70) and SP-3 fraction (fraction numbers 71-100) were collected and concentrated as each peptide fraction. Each peptide powder (SP fraction) was obtained by lyophilization. Among peptide powders (SP fraction) obtained by fractionation in this way, 7 mg of peptide powder of SP-3 fraction having high prolyl endopeptidase inhibitory activity was dissolved in 25 μL of deionized water, Liquid chromatography (HPLC) was performed. As HPLC conditions, Develosil ODS-5 (φ4.6 mm ID × 25 cmL) manufactured by Nomura Chemical Co., Ltd. was used as a column, and 0.05% trifluoroacetic acid (hereinafter abbreviated as TFA) as a mobile phase to 25% acetonitrile / Chromatography was performed at a flow rate of 1.0 mL / min and a detection wavelength of 220 nm by a concentration gradient method using 0.05% TFA, and the elution time was 21.0 minutes (1), 26.7 minutes (2), and 42.9 minutes. Peptide fragments having strong prolyl endopeptidase inhibitory activity were obtained at (3) and 53.1 minutes (4).
The amino acid sequence of the prolyl endopeptidase-inhibiting peptide thus obtained was determined using a protein sequencer type 477A manufactured by Applied Biosystems (ABI). As a result, the following formulas (1) (2) (3) and (4)
(1) Ile-Gly-Phe-Pro-Leu-Pro
(2) Ala-Ile-Leu-Pro-Pro
(3) Ile-His-Val-Pro-Pro
(4) Ile-Thr-Pro-Pro-Pro
It was confirmed that it is a novel peptide represented by the amino acid sequence of L-form represented by The property at room temperature is a white powder. In addition, when a novel peptide according to the present invention is formulated as a prolyl endopeptidase inhibitor, for example, into a tablet, it may be treated according to a conventional method, for example, as follows: (1) 10 g of peptide, (2) 80g of lactose, (3) 20g of corn starch, (4) 1.0g of magnesium stearate, first mix (1), (2) and 20g of corn starch, granulate with the paste made from 8g of corn starch, 6 g of corn starch and (4) are added to the granules, and the resulting mixture is compressed with a compression tablet machine to produce 1000 tablets.

Production Example 2
This example is an example of production by a synthesis method.
Synthesis method of Ile-Gly-Phe-Pro-Leu-Pro The peptide was synthesized by a solid phase method using a peptide synthesizer 430A type manufactured by Applied Biosystems (ABI). As the solid support, a resin obtained by chloromethylating a styrene-divinylbenzene copolymer (polystyrene resin) was used. First, according to the amino acid sequence of the peptide, the C-terminal proline was reacted with a chloromethyl resin in the usual manner to obtain a peptide-bonded resin. As the amino acid at this time, a t-Boc amino acid protected with a t-butoxycarbonyl (hereinafter abbreviated as t-Boc) group was used. Next, this peptide-bonded resin was suspended in a mixed solution composed of ethanediol and thioanisole, stirred for 10 minutes at room temperature, added with trifluoroacetic acid under ice cooling, and further stirred for 10 minutes. Trifluoromethanesulfonic acid was added dropwise to the mixture, and the mixture was stirred at room temperature for 30 minutes. Then, anhydrous ether was added to precipitate the product, and the precipitate was washed several times with anhydrous ether. Dried. The crude synthetic peptide thus obtained was dissolved in distilled water and then purified by HPLC using a reverse phase system column C ₁₈ (5 μm). (A) 0.1% TFA-containing distilled water and (B) 0.1% TFA-containing acetonitrile solution were used as the mobile phase, and (A) the flow rate was 1 by the concentration gradient method of 80% -55% in 42 minutes. Chromatography at 8 mL / min. The elution fraction detected at the ultraviolet wavelength of 217 nm and exhibiting the maximum absorption was collected and freeze-dried to obtain the intended synthetic peptide.

Ala-Ile-Leu-Pro-Pro Synthesis Method The peptide was synthesized by a solid phase method using a peptide synthesizer type 430A manufactured by Applied Biosystems (ABI). As the solid support, a resin obtained by chloromethylating a styrene-divinylbenzene copolymer (polystyrene resin) was used. First, according to the amino acid sequence of the peptide, the C-terminal proline was reacted with a chloromethyl resin in the usual manner to obtain a peptide-bonded resin. As the amino acid at this time, a t-Boc amino acid protected with a t-butoxycarbonyl (hereinafter abbreviated as t-Boc) group was used. Next, this peptide-bonded resin was suspended in a mixed solution composed of ethanediol and thioanisole, stirred for 10 minutes at room temperature, added with trifluoroacetic acid under ice cooling, and further stirred for 10 minutes. Trifluoromethanesulfonic acid was added dropwise to the mixture, and the mixture was stirred at room temperature for 30 minutes. Then, anhydrous ether was added to precipitate the product, and the precipitate was washed several times with anhydrous ether. And dried. The crude synthetic peptide thus obtained was dissolved in distilled water and then purified by HPLC using a reverse phase system column C ₁₈ (5 μm). (A) 0.1% TFA-containing distilled water and (B) 0.1% TFA-containing acetonitrile solution were used as the mobile phase, and (A) the flow rate was 1% by a gradient method of 79% -65% in 51 minutes. Chromatography at 9 mL / min. The elution fraction detected at the ultraviolet wavelength of 218 nm and exhibiting the maximum absorption was collected and lyophilized to obtain the target synthetic peptide.

Synthesis method of Ile-His-Val-Pro-Pro The peptide was synthesized by a solid phase method using a peptide synthesizer type 430A manufactured by Applied Biosystems (ABI). As the solid support, a resin obtained by chloromethylating a styrene-divinylbenzene copolymer (polystyrene resin) was used. First, according to the amino acid sequence of the peptide, the C-terminal proline was reacted with a chloromethyl resin in the usual manner to obtain a peptide-bonded resin. As the amino acid at this time, a t-Boc amino acid protected with a t-butoxycarbonyl (hereinafter abbreviated as t-Boc) group was used. Next, this peptide-bonded resin was suspended in a mixed solution composed of ethanediol and thioanisole, stirred for 10 minutes at room temperature, added with trifluoroacetic acid under ice cooling, and further stirred for 10 minutes. Trifluoromethanesulfonic acid was added dropwise to the mixture, and the mixture was stirred at room temperature for 30 minutes. Then, anhydrous ether was added to precipitate the product, and the precipitate was washed several times with anhydrous ether. And dried. The crude synthetic peptide thus obtained was dissolved in distilled water and then purified by HPLC using a reverse phase system column C ₁₈ (5 μm). (A) 0.1% TFA-containing distilled water and (B) 0.1% TFA-containing acetonitrile solution were used as the mobile phase, and (A) liquid was flowed at a flow rate of 1 by a concentration gradient method of 79% -63% over 41 minutes. Chromatography at 7 mL / min. The elution fraction detected at the ultraviolet wavelength of 217 nm and exhibiting the maximum absorption was collected and freeze-dried to obtain the intended synthetic peptide.

Synthesis method of Ile-Thr-Pro-Pro-Pro The peptide was synthesized by a solid phase method using a peptide synthesizer type 430A manufactured by Applied Biosystems (ABI). As the solid support, a resin obtained by chloromethylating a styrene-divinylbenzene copolymer (polystyrene resin) was used. First, according to the amino acid sequence of the peptide, the C-terminal proline was reacted with a chloromethyl resin in the usual manner to obtain a peptide-bonded resin. As the amino acid at this time, a t-Boc amino acid protected with a t-butoxycarbonyl (hereinafter abbreviated as t-Boc) group was used. Next, this peptide-bonded resin was suspended in a mixed solution composed of ethanediol and thioanisole, stirred for 10 minutes at room temperature, added with trifluoroacetic acid under ice cooling, and further stirred for 10 minutes. Trifluoromethanesulfonic acid was added dropwise to the mixture, and the mixture was stirred at room temperature for 30 minutes. Then, anhydrous ether was added to precipitate the product, and the precipitate was washed several times with anhydrous ether. And dried. The crude synthetic peptide thus obtained was dissolved in distilled water and then purified by HPLC using a reverse phase system column C ₁₈ (5 μm). (A) Distilled water containing 0.1% TFA and (B) 0.1% TFA-containing acetonitrile solution were used as the mobile phase, and (A) the flow rate was 2 by a concentration gradient method of 83% -69% over 43 minutes. Chromatography at 1 mL / min. The elution fraction detected at the ultraviolet wavelength of 218 nm and exhibiting the maximum absorption was collected and lyophilized to obtain the target synthetic peptide.

Thus, the novel peptide based on this invention obtained by the synthesis | combination confirmed the prolyl endopeptidase inhibitory ability by the in vitro test shown below.
Test Example 1 (Prolyl Endopeptidase Inhibitory Activity Measurement Method)
Enzyme: Prolyl endopeptidase (manufactured by Seikagaku Corporation, enzyme number EC 3.4.21.26) 0.1 U / mL, synthetic substrate Z-Gly-L-Pro-pNA (manufactured by Seikagaku Corporation) 2 mM , Measured according to the method of Yoshimoto et al. [Non-patent Document 3]. That is, 2000 μL of 0.1 M phosphate buffer (pH 7.0), 100 μL of a test solution (synthetic peptide), and 100 μL of an enzyme solution (containing 40% dioxane) were sequentially added and preincubated at 30 ° C. for 5 minutes. Further, 100 μL of the substrate solution was added and incubated at 30 ° C. for 10 minutes. Thereafter, the reaction was stopped by adding 500 μL of 1N HCl, and the absorbance at 410 nm was measured. The inhibition rate was calculated from the following equation, where Es is the absorbance in the test solution, Ec is the value when the buffer solution is added instead of the test solution, and Eb is the value when the reaction stop solution is added and reacted in advance. .
Inhibition rate (%) = (Ec−Es) / (Ec−Eb) × 100
The inhibitory activity IC ₅₀ value of the prolyl endopeptidase inhibitor was expressed as the concentration (M) of the test solution necessary to inhibit the enzyme activity of prolyl endopeptidase by 50% (inhibition rate).

前記合成によって得られた本発明に係る新規なペプチドは、以下に示すｉｎ ｖｉｖｏ（生体内）試験によって薬理効果が確認された。As a result of analyzing the novel peptide according to the present invention obtained by the synthesis by mass spectrum and amino acid analysis, it was confirmed that the amino acid sequence and amino acid composition were peptides having the amino acid sequence structure shown above. The results of the mass spectrum and amino acid analysis are as shown in Table 1. At the same time, the prolyl endopeptidase inhibitory activity values of the novel peptides according to the present invention obtained by the synthesis are shown in Table 1.

The pharmacological effect of the novel peptide according to the present invention obtained by the synthesis was confirmed by the following in vivo test.

本発明に係る新規なペプチドは、ｉｎ ｖｉｔｒｏ（試験管内）においてプロリルエンドペプチダーゼ阻害活性を有し、ｉｎ ｖｉｖｏ（生体内）においても有意な抗健忘症効果を示すことが確認された。従って、本発明に係る新規なペプチドは痴呆症の治療又は予防薬として有用である。尚、本発明に係る新規なペプチドは、構造的にそのアミノ酸配列を部分構造とするペプチドにおいて、構造中に採用することもできる。Test Example 2 (Anti-amnesic effect test using rats)
The anti-amnesic effect test of the novel peptide according to the present invention obtained by the above synthesis is performed using a rat passive avoidance learning apparatus, that is, a foot shock stress system (MFS-01, MFS-01). It was. The experimental animals were purchased from Kyushu Co., Ltd., 4 male male rats (average body weight 160 g), 3 rats each in 3 groups, and then a passive avoidance learning test was conducted. Rats orally administered with saline as an intact control (saline group), rats orally administered with 0.2 mg / kg of donepezil hydrochloride (manufactured by Eisai Co., Ltd.) as a control, and 200 mg / kg of synthetic peptide Experiments were conducted using rats orally administered with kg (synthetic peptide group). Each of these three groups of rats is placed on a table, and a current is passed from the moment of getting down to the floor, returning to the table to avoid an electric shock, and passive avoidance learning until it no longer gets down to the floor. Next, when 20 mg / kg of scopolamine causing dementia is administered to these three groups of rats, the previous electric shock is forgotten and the patient comes down to the floor. By measuring the residence time (seconds) until the rat descended to the floor, it was examined how much the synthetic peptide administered before learning prevented this memory loss. The results of the above test are shown in Table 2.

It was confirmed that the novel peptide according to the present invention has a prolyl endopeptidase inhibitory activity in vitro (in vitro) and exhibits a significant anti-amnesic effect also in vivo (in vivo). Therefore, the novel peptide according to the present invention is useful as a therapeutic or prophylactic agent for dementia. In addition, the novel peptide which concerns on this invention can also be employ | adopted in a structure in the peptide which has the amino acid sequence as a partial structure structurally.

Claims (8)

The following formula: Ile-Gly-Phe-Pro-Leu-Pro
A novel peptide having a peptide structure according to the amino acid sequence of L-form represented by The following formula: Ile-Gly-Phe-Pro-Leu-Pro
A prolyl endopeptidase inhibitor comprising a novel peptide having a peptide structure based on the L-amino acid sequence represented by The following formula: Ala-Ile-Leu-Pro-Pro
A novel peptide having a peptide structure according to the amino acid sequence of L-form represented by The following formula: Ala-Ile-Leu-Pro-Pro
A prolyl endopeptidase inhibitor comprising a novel peptide having a peptide structure based on the L-amino acid sequence represented by The following formula: Ile-His-Val-Pro-Pro
A novel peptide having a peptide structure according to the amino acid sequence of L-form represented by The following formula: Ile-His-Val-Pro-Pro
A prolyl endopeptidase inhibitor comprising a novel peptide having a peptide structure based on the L-amino acid sequence represented by The following formula: Ile-Thr-Pro-Pro-Pro
A novel peptide having a peptide structure according to the amino acid sequence of L-form represented by The following formula: Ile-Thr-Pro-Pro-Pro
A prolyl endopeptidase inhibitor comprising a novel peptide having a peptide structure based on the L-amino acid sequence represented by