KR20170019993A - Composition for preventing or treating Alzheimer's disease induced by halocynthia aurantium muscle hydrolysates - Google Patents

Composition for preventing or treating Alzheimer's disease induced by halocynthia aurantium muscle hydrolysates Download PDF

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KR20170019993A
KR20170019993A KR1020150114594A KR20150114594A KR20170019993A KR 20170019993 A KR20170019993 A KR 20170019993A KR 1020150114594 A KR1020150114594 A KR 1020150114594A KR 20150114594 A KR20150114594 A KR 20150114594A KR 20170019993 A KR20170019993 A KR 20170019993A
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이정권
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강릉원주대학교산학협력단
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Abstract

The present invention relates to a composition for inhibiting or preventing Alzheimers disease containing peptide, obtained by hydrolyzing protein induced by Halocynthia aurantium muscle hydrolysates, as an active ingredient.

Description

붉은멍게 근육 가수분해물 유래의 항알츠하이머성 펩타이드 조성물{Composition for preventing or treating Alzheimer's disease induced by halocynthia aurantium muscle hydrolysates}[0001] The present invention relates to an anti-Alzheimer's peptide composition derived from a red rhubarb muscle hydrolyzate,

본 발명은 붉은멍게 근육 가수분해물 유래의 항알츠하이머성 펩타이드 조성물에 관한 것이다. The present invention relates to an anti-Alzheimer's peptide composition derived from a red rhizome muscle hydrolyzate.

알츠하이머병(AD)은 신경세포 손상으로 인해 기억력, 인지력, 추론력, 판단력 및 지남력의 상실을 특징으로 하는 노화와 밀접한 관련이 있는 퇴행성 뇌질환이다. 알츠하이머병의 병리학적 특징으로 뇌의 인지활동과 관련된 영역에서 신경섬유다발의 세포내 축적과, Aβ 단백질이 주요성분으로 구성된 노인반점(senile plaque)의 세포외 침착을 나타낸다. 39-43개의 아미노산으로 구성된 Aβ 단백질은 신경세포 독성을 나타내는 것이 공지되어 있다. 다수의 보고에 의하면 Aβ는 알츠하이머병의 병리적 특징이며, 병의 발생의 주요원인으로 인식되고 있다. Aβ 펩티드는 아밀로이드 전구체 단백질(Amyloid precursor protein, 이하, APP라 함)의 가수분해에 의해 생성되며, 39-43개의 아미노산으로 이루어진 다수의 Aβ가 알려져 있다. APP가 먼저 BACE에 의해 아밀로이드 전구체 단백질(APP)의 N-말단에서 절단 된 후 감마-세크레타아제에 의해 C-말단에서 절단되는 경로에 의해 Aβ가 생성된다. Alzheimer's disease (AD) is a degenerative brain disease closely related to aging characterized by loss of memory, cognition, reasoning, judgment and disposition due to neuronal damage. The pathological features of Alzheimer's disease are intracellular accumulation of nerve fiber bundles in the area associated with cognitive activity in the brain and extracellular deposition of senile plaques composed of Aβ protein as a major component. It is known that A [beta] proteins composed of 39-43 amino acids show neuronal cytotoxicity. A number of reports have shown that Aβ is a pathological feature of Alzheimer's disease and is recognized as a major cause of disease development. A [beta] peptide is produced by hydrolysis of an amyloid precursor protein (hereinafter abbreviated as APP), and a large number of A [beta] consisting of 39-43 amino acids is known. Ap is first cleaved at the N-terminus of the amyloid precursor protein (APP) by BACE and then cleaved at the C-terminus by gamma-secrecase.

따라서, BACE, Asp 또는 메맙신(Memapsin)으로도 명명되고 있는 베타-세크레타아제 효소((a) Tang, J. et al., Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 1456. (b) Hussain, I. et al., Mol. CellNeurosci.1999, 14, 419. (c) Yan, R. et al., Nature1999, 402, 533. (d). Sinha, S, et al., Nature1999, 402, 537. (e) Vassar, R.et al., Science1999, 286, 735.)의 활성을 억제하는 저해제는 알츠하이머 질환의 예방 및 근본적인 발병원인이나 증상을 치료할 수 있는 약물로 사용가능하므로, 현재 수많은 제약회사에서 새로운 저해제를 개발하기 위하여 노력하고 있다. Thus, the beta-secretase enzyme (also referred to as BACE, Asp, or Memapsin) ((a) Tang, J. et al., Proc. Natl. Acad Sci. USA 2000, 97, 1456 b) Hussain, I. et al., Mol. Cell Neurosci. 1999, 14, 419. (c) Yan, R. et al., Nature 1999, 402, 533. (d) Sinha, S, et al., Nature 1999 , 402, 537. (e) Vassar, R. et al., Science 1999, 286, 735.) can be used as a drug capable of treating the preventive and fundamental cause of Alzheimer's disease or symptoms, Numerous pharmaceutical companies are currently working to develop new inhibitors.

본 발명에서는 붉은멍게 근육 가수분해물 유래의 항알츠하이머성 펩타이드 조성물을 제공한다. The present invention provides an anti-Alzheimer's peptide composition derived from red ginseng muscle hydrolysates.

본 발명은 붉은멍게 근육 유래의 단백질을 가수분해하여 얻어지는 펩타이드를 유효 성분으로 함유하는 알츠하이머 질병(Alzheimer's disease)의 억제 또는 예방용 조성물을 제공한다. The present invention provides a composition for inhibiting or preventing Alzheimer's disease, which contains, as an active ingredient, a peptide obtained by hydrolyzing a protein derived from red mulberry muscle.

본 발명에 따른 조성물은 알츠하이머 질병(Alzheimer's disease)의 억제 또는 예방에 효과적이다. The composition according to the present invention is effective for inhibiting or preventing Alzheimer ' s disease.

도 1은 붉은멍게 근육의 구성 아미노산 조성을 나타내는 그래프이다.
도 2는 붉은멍게 근육 가수분해물로부터 베타-시크리타아제 저해 펩타이드 분리정제 과정을 나타내는 그래프로, (A) 세파덱스 G-25 컬럼 크로마토그래피를 이용한 분리정제, (B,C) HPLC를 이용한 분리정제 과정을 나타낸다.
도 3은 붉은멍게 근육 유래의 가수분해산물 분획성분을 대상으로 MS/MS 분석 결과를 도시한 그래프이다. FIG. 1 is a graph showing the compositional composition of amino acids of the red squid muscle.
FIG. 2 is a graph showing a process for separating and purifying a beta-secretase inhibitor from red rotifer muscle hydrolyzate. (A) Separation purification using Sephadex G-25 column chromatography, (B, C) Process.
FIG. 3 is a graph showing the results of MS / MS analysis of a hydrolyzate fraction component derived from a red barb muscle.

본 발명은 붉은멍게 근육 유래의 단백질을 가수분해하여 얻어지는 펩타이드를 유효 성분으로 함유하는 알츠하이머 질병(Alzheimer'sdisease)의 억제 또는 예방용 조성물에 관한 것이다.The present invention relates to a composition for inhibiting or preventing Alzheimer's disease, which contains, as an active ingredient, a peptide obtained by hydrolyzing a protein derived from red mulberry muscle.

본 발명에서 펩타이드는 상기 붉은멍게 근육을 이루는 단백질을 단백질 가수분해효소로 처리한 가수분해 산물일 수 있다. In the present invention, the peptide may be a hydrolyzate obtained by treating a protein constituting the red squid muscle with a protein hydrolyzing enzyme.

상기 조성물은 베타-시크레타제(β-secretase) 억제 활성을 가질 수 있다. The composition may have a beta-secretase inhibitory activity.

상기 붉은멍게 근육에서 유래된 펩타이드를 함유하는 유효 성분은 0.001 내지 10.0 ㎎/㎖의 농도로 포함될 수 있다. The active ingredient containing the peptide derived from the red squid muscle may be contained at a concentration of 0.001 to 10.0 mg / ml.

상기 붉은멍게 근육에서 유래된 펩타이드는 서열번호 1의 아미노산 서열을 가질 수 있다. The peptide derived from the red squid muscle may have the amino acid sequence of SEQ ID NO: 1.

서열번호1: LVKVEASEQ ID NO: 1: LVKVEA

또한, 조성물의 아미노산 중 N-말단에 류신(Leucine)이 결합될 수 있다. Leucine may also be bonded to the N-terminus of the amino acid of the composition.

실시예 Example

1. 붉은멍게 근육의 아미노산 조성1. Amino acid composition of red squid muscle

붉은 멍게 근육의 아미노산 조성 분석 결과를 도 1에 나타내었다. 붉은 멍게의 주요아미노산은 Gly(13.0%), Glu(13.22%) 및 Asp(11.1%)로 나타났다. Fig. 1 shows the results of analysis of the amino acid composition of the red squid muscle. Gly (13.0%), Glu (13.22%) and Asp (11.1%) were the major amino acids of the red sea squirt.

2. 붉은멍게 근육 유래의 효소적 단백질 가수분해물 제조2. Preparation of Enzymatic Protein Hydrolyzate from Red Muscle Muscle

붉은멍게 근육의 단백질 및 콜라겐을 이용하기 위하여 단백질 가수분해 효소를 이용하여 가수분해를 실시 한 후 가수분해도를 측정하였다. 단백질 가수분해 효소는 Alcalase, α-chymotrypsin, Neutrase, papain, pepsin 및 trypsin을 사용하였다. 어류의 근육1.0g를 100ml의 buffer에 넣고 pH와 온도를 각 효소의 최적 조건에 맞추어 1시간 반응시킨 후 효소대 기질을 1:100 비율로 효소를 넣어 준 후 12시간 반응 시켰다. 가수분해 효소별 조건은 표1에 나타내었다. 12시간 반응 후 원심분리하여 상등액을 수거하고, 수거된 상등액은 동결건조하여 β-secretase 활성 측정에 사용하였다. 각 가수분해물의 가수분해도를 측정한 결과, chymotrypsin 가수분해물의 가수분해도가 52.62%로 가장 우수하였다(표2).Protein and collagen of red squid muscle were hydrolyzed by proteolytic enzyme and hydrolysis was measured. Alcalase, α-chymotrypsin, Neutrase, papain, pepsin and trypsin were used as protein hydrolytic enzymes. 1.0 g of fish muscle was added to 100 ml of buffer, and the pH and temperature were adjusted to the optimum conditions for 1 hour. The reaction was carried out for 1 hour at a ratio of 1: 100. Conditions for hydrolytic enzymes are shown in Table 1. After 12 hours of reaction, the supernatant was collected by centrifugation, and the collected supernatant was used for β-secretase activity measurement by lyophilization. The hydrolysis rate of each hydrolyzate was measured, and the hydrolysis rate of chymotrypsin hydrolyzate was the highest at 52.62% (Table 2).

EnzymeEnzyme BufferBuffer pHpH Temperature (℃)Temperature (° C) AlcalaseAlcalase 50mM sodium phosphate50 mM sodium phosphate 7.07.0 5050 αchymotrypsinalpha chymotrypsin 50mM sodium phosphate50 mM sodium phosphate 8.08.0 3737 NeutraseNeutrase 50mM sodium phosphate50 mM sodium phosphate 8.08.0 5050 PapainPapain 50mM sodium phosphate50 mM sodium phosphate 6.06.0 3737 PepsinPepsin 20mM glycineHCl20 mM glycine HCl 2.02.0 3737 TrypsinTrypsin 50mM sodium phosphate50 mM sodium phosphate 8.08.0 3737

Degree of hydrolysis (%)Degree of hydrolysis (%) AlcalaseAlcalase 37.1937.19 ChymotrypsinChymotrypsin 52.6252.62 NeutraseNeutrase 40.8140.81 PapainPapain 24.0124.01 PepsinPepsin 25.9525.95 TrypsinTrypsin 48.4248.42

3. 붉은멍게 근육 가수분해물의 β-secretase 저해활성3. β-secretase inhibitory activity of the hydrolysates of the muscovite muscles

β-secretase inhibitory activity assay를 이용하여 각 가수분해물 중 β-secretase 저해 활성이 높은 펩타이드가 다량 함유되어 있는 효소 가수분해물을 선정한다. β-secretase inhibitory activity은 β-secretase assay kit에서 제시한 방법을 변형하여 측정한다. 즉, 70μl buffer (50mM sodium acetate, pH 4.5), 10μl β-secretase (1.0 Unit/ml), 10μl substrate (10mM MCA-[ASN670, LEU671]-AMYLOID BETA/A4 PRECURSOR PROTEIN 77, 50mM sodium acetate buffer, pH 4.5)를 10μl의 시료액과 혼합 후 25℃에서 60분간 암조건에서 반응시킨다. 형광 reader(Bio-Rad)는 excitation 360nm로 하고, emission 405nm로 하여 측정한다. 저해율 공식은 다음과 같다.β-secretase inhibitory activity assay is used to select enzyme hydrolysates containing large amounts of peptides with high β-secretase inhibitory activity among the hydrolysates. β-secretase inhibitory activity is measured by modifying the method proposed in the β-secretase assay kit. (50 μM sodium acetate, pH 4.5), 10 μl β-secretase (1.0 Unit / ml), 10 μl substrate (10 mM MCA- [ASN670, LEU671] -AMYLOID BETA / A4 PRECURSOR PROTEIN 77, 50 mM sodium acetate buffer, pH 4.5) was mixed with 10 μl of the sample solution and reacted at 25 ° C for 60 minutes under dark condition. The fluorescence reader (Bio-Rad) is measured with an excitation of 360 nm and an emission of 405 nm. The inhibition rate formula is as follows.

Inhibition (%) = [1-{(S-S0)/(C-C0)}]×100Inhibition (%) = [1 - {(S-S0) / (C-C0)}] 100

C :　(Enzyme + buffer + substrate) 반응 20분 후 C: (Enzyme + buffer + substrate) After 20 minutes of reaction

C0:(Enzyme+buffer+substrate)반응 직전 (zero time)C0: (Enzyme + buffer + substrate)

S : (Enzyme + sample + substrate) 반응 20분 후S: (Enzyme + sample + substrate) After 20 minutes of reaction

S0:(Enzyme+sample+substrate)반응 직전 (zero time)S0: (Enzyme + sample + substrate)

붉은멍게 근육의 각 가수분해물의 β-secretase 저해활성은 IC50값으로 측정하여 표3에 나타내었다. 가수분해물 중에서 β-secretase 저해활성은 Alcalase 가수분해물의 IC50값이 1.23mg/ml로 다른 가수분해물에 비해 높게 나타났다(표 3).The β-secretase inhibitory activity of each hydrolyzate of red squid muscle was measured by IC50 value and shown in Table 3. Among the hydrolysates, the β-secretase inhibitory activity of the Alcalase hydrolyzate was 1.23 mg / ml, which was higher than other hydrolysates (Table 3).

IC50 value (mg/ml)IC 50 value (mg / ml) AlcalaseAlcalase 1.231.23 ChymotrypsinChymotrypsin 1.761.76 NeutraseNeutrase 1.431.43 PapainPapain 1.601.60 PepsinPepsin 2.502.50 TrypsinTrypsin 8.098.09

4. β-secretase 저해 펩타이드의 분리정제4. Isolation and purification of β-secretase inhibitory peptide

붉은멍게 근육 가수분해물 중에서 β-secretase 저해활성이 가장 우수한 Alcalase 가수분해물로부터 β-secretase 저해 펩타이드를 분리정제하였다. Alcalase 분해된 붉은멍게 근육 가수분해물을 100mg/ml 농도로 탈이온수에 녹인 후 Sephadex G-25를 충진시킨 column(2.5 × 75cm)에 주입하였다. 분리용매는 탈이온수를 이용하여 1.5ml/min 유속으로 분리하였으며, 흡광도 215nm에서 결과를 측정하여 각 획분으로 분리하였다. 분리결과, 4개의 획분(F1~F4)을 얻었으며, 4개의 분획물 중에서 β-secretase 저해 활성은 획분 F3의 IC50값이 987μg/ml으로 가장 높게 나타났다. β-secretase 저해 활성이 가장 높은 획분 F3는 ODS column (5μm, 10 × 250mm, YMC, lnc. Japan)를 사용하여 Agilent 1000 HPLC에서 분리정제 하였다, 분리용매는 acetonitrile (0.1% trichloroacetic acid)를 40분간 0%에서 20%로 농도구배를 하여 2.0ml/min의 유속으로 분리하였다. 분리결과는 흡광도 215nm에서 측정하여 그래프로 나타냈다. 분리 결과는 3개의 획분(F1~F3)으로 분리되었다. 각 획분의 β-secretase 저해활성은 획분 F1의 IC50 값이 115.1μg/ml로 가장 높게 나타났다. β-secretase 저해활성이 가장 높은 획분 F1는 다시 HPLC에서 분석용 column (particle size 5 μm; 4.6×250 mm)를 사용하여 유속 0.5ml/min의 조건으로 분리하였다. 분리결과는 흡광도 215nm에서 측정하여 그래프로 나타냈었다. 재 분리정제 결과, F1-1 획분의 단일 펩타이드로 분리되었다.  Β-secretase inhibitory peptides were isolated and purified from Alcalase hydrolyzate, which has the highest β-secretase inhibitory activity. Alcalase hydrolyzate was dissolved in deionized water at a concentration of 100 mg / ml and then injected into a column (2.5 × 75 cm) packed with Sephadex G-25. The separation solvent was separated by using a deionized water at a flow rate of 1.5 ml / min and the result was measured at an absorbance of 215 nm. As a result of the separation, four fractions (F1 to F4) were obtained. Among the four fractions, the β-secretase inhibitory activity showed the highest IC50 value of fraction F3 of 987 μg / ml. The fraction F3 with the highest β-secretase inhibitory activity was separated and purified on an Agilent 1000 HPLC using an ODS column (5 μm, 10 × 250 mm, YMC, Japan). The separation solvent was acetonitrile (0.1% trichloroacetic acid) The concentration gradient from 0% to 20% was carried out at a flow rate of 2.0 ml / min. The separation results were plotted as measured at an absorbance of 215 nm. The separation results were separated into three fractions (F1 to F3). The β-secretase inhibitory activity of each fraction showed the highest IC50 value of fraction F1 of 115.1 μg / ml. The fraction F1 with the highest β-secretase inhibitory activity was further separated by HPLC using a column for analysis (particle size 5 μm; 4.6 × 250 mm) at a flow rate of 0.5 ml / min. The separation results were plotted as absorbance at 215 nm. As a result of re-separation purification, it was separated into a single peptide of F1-1 fraction.

5. β-secretase 저해 펩타이드의 분자량 및 아미노산 서열5. Molecular weight and amino acid sequence of? -Secretase inhibitory peptide

아미노산 서열 분석은 순차적으로 nano Ultra Performance Liquid Chromatography(nanoUPLC, Waters Corporation, Milford, MA) 와 연결된 nano-전자분부(ESI) 사극 자(quadrupole) 이온 비행 시간차 분석기(TOF) 질량분석기(Q-TOF Premier, Waters Corporation, Manchester, UK)에 의하여 분석이 이루어졌다. 모든 분석은 양이온 모드로 분석하였다. 이때 scan은 0.6초 간격으로, MS spectra는 m/z 100에서 m/z 1,600의 범위에서 분석하였다. 이때 초당 이온 검출 강도 20 이상인 이온 중, 가장 높은 강도를 보이는 3개를 선택하여 이온 비행 시간차 분석기를 통해 m/z 50 에서 m/z 1,990 범위에서 1.2초 동안 MS/MS spectra를 받았다. 데이터 수집은 초당 이온 검출 강도 20 이상인 이온을 선택하여 분석한다. 분석한 결과 (도3), 붉은멍게 근육 가수분해물로부터 분리된 활성 펩타이디는 Leu-Val-Lys-Val-Glu-Ala (657.8Da)의 6개의 아미노산 잔기를 가지고 있으며, β-secretase 저해 활성 펩타이드의 IC50값은 159.25 μM이였다. Amino acid sequence analysis was performed using a nano-electronic fractionation (ESI) quadrupole ion flight time-of-flight analyzer (TOF) mass spectrometer (Q-TOF Premier) coupled with nano Ultra Performance Liquid Chromatography (nanoUPLC, Waters Corporation, Milford, MA) Waters Corporation, Manchester, UK). All analyzes were analyzed in cationic mode. At this time, the scan was analyzed at 0.6 second intervals, and the MS spectra was analyzed in the range of m / z 100 to m / z 1,600. Among the ions with a detection strength of 20 or more per second, three of the highest intensities were selected and received MS / MS spectra for 1.2 seconds at m / z 50 to m / z 1,990 through an ion flight time analyzer. Data collection is performed by selecting ions with an ion detection strength of 20 or more per second. (Fig. 3). The active peptidases isolated from the skeletal muscle hydrolyzate have six amino acid residues of Leu-Val-Lys-Val-Glu-Ala (657.8 Da) The IC50 value of the peptide was 159.25 [mu] M.

Claims (6)

붉은멍게 근육 유래의 단백질을 가수분해하여 얻어지는 펩타이드를 유효 성분으로 함유하는 알츠하이머 질병(Alzheimer's disease)의 억제 또는 예방용 조성물.
A composition for inhibiting or preventing Alzheimer's disease comprising, as an active ingredient, a peptide obtained by hydrolyzing a protein derived from red mullet muscle.
제 1항에 있어서,
펩타이드는 상기 붉은멍게 근육을 이루는 단백질을 단백질 가수분해효소로 처리한 가수분해 산물인 조성물.
The method according to claim 1,
Wherein the peptide is a hydrolyzate obtained by treating a protein constituting the red squid muscle with a protein hydrolyzing enzyme.
제 1항에 있어서,
조성물은 베타-시크레타제(β-secretase) 억제 활성을 갖는 조성물.
The method according to claim 1,
Wherein the composition has a beta-secretase inhibitory activity.
제 1항에 있어서,
붉은멍게 근육에서 유래된 펩타이드를 함유하는 유효 성분은 0.001 내지 10.0 ㎎/㎖의 농도로 포함되는 조성물.
The method according to claim 1,
Wherein the active ingredient containing the peptides derived from the red mullet muscle is contained in a concentration of 0.001 to 10.0 mg / ml.
제 1항에 있어서,
붉은멍게 근육에서 유래된 펩타이드는 서열번호 1의 아미노산 서열을 갖는 조성물.
The method according to claim 1,
The peptide derived from the red rhyming muscle has the amino acid sequence of SEQ ID NO: 1.
제 1항에 있어서,
조성물의 아미노산 중 N-말단에 류신(Leucine)이 결합된 것인 조성물.
The method according to claim 1,
Wherein the amino acid of the composition is conjugated to Leucine at its N-terminus.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20080029370A (en) * 2006-09-29 2008-04-03 한국과학기술연구원 Pharmaceutical composition comprising an extract from opuntia ficus-indica
KR20120032893A (en) * 2010-09-29 2012-04-06 강릉원주대학교산학협력단 Composition extracted from skate skin for inhibiting or preventing alzheimer's disease
KR20130029166A (en) * 2011-09-14 2013-03-22 강릉원주대학교산학협력단 Pharmaceutical composition and functional food having anti-alzheimer activity containing peptides from fish skins

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20080029370A (en) * 2006-09-29 2008-04-03 한국과학기술연구원 Pharmaceutical composition comprising an extract from opuntia ficus-indica
KR20120032893A (en) * 2010-09-29 2012-04-06 강릉원주대학교산학협력단 Composition extracted from skate skin for inhibiting or preventing alzheimer's disease
KR20130029166A (en) * 2011-09-14 2013-03-22 강릉원주대학교산학협력단 Pharmaceutical composition and functional food having anti-alzheimer activity containing peptides from fish skins

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