JP2023144717A - Angiotensin-converting enzyme inhibitory peptide - Google Patents
Angiotensin-converting enzyme inhibitory peptide Download PDFInfo
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- JP2023144717A JP2023144717A JP2022051836A JP2022051836A JP2023144717A JP 2023144717 A JP2023144717 A JP 2023144717A JP 2022051836 A JP2022051836 A JP 2022051836A JP 2022051836 A JP2022051836 A JP 2022051836A JP 2023144717 A JP2023144717 A JP 2023144717A
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- Prior art keywords
- converting enzyme
- angiotensin
- peptide
- present
- active ingredient
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Landscapes
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
本発明は、新規なペプチドに関する。また、本発明は新規なペプチドを有効成分として含有するアンジオテンシン変換酵素阻害剤及びアンジオテンシン変換酵素阻害用飲食品に関する。 The present invention relates to novel peptides. The present invention also relates to an angiotensin-converting enzyme inhibitor and an angiotensin-converting enzyme-inhibiting food or drink containing a novel peptide as an active ingredient.
アンジオテンシン変換酵素（ＡＣＥ）は、血圧の調節においてレニン－アンジオテンシン系に作用する酵素である。分子量約57,000のアンジオテンシノーゲンは、腎臓から血管中に移行するレニンによりアンジオテンシンＩに変換される。このアンジオテンシンＩは、殆ど血管収縮作用を示さない不活性型であるが、アンジオテンシン変換酵素は強い昇圧作用を有するアンジオテンシンIIを生成させるとともに、降圧作用を有するブラジキニンを不活性化する作用も有している。このような作用から、アンジオテンシン変換酵素阻害剤は、高血圧の治療薬として使用されており市販薬として知られている。また、アンジオテンシン変換酵素阻害剤は、心疾患、腎疾患、脳血管障害、動脈硬化性疾患、糖尿病、メタボリックシンドローム、高齢者高血圧など多くの病態に対して使用されている。 Angiotensin-converting enzyme (ACE) is an enzyme that acts on the renin-angiotensin system in regulating blood pressure. Angiotensinogen, which has a molecular weight of about 57,000, is converted to angiotensin I by renin, which moves from the kidneys into the blood vessels. This angiotensin I is an inactive type that shows almost no vasoconstriction effect, but angiotensin converting enzyme produces angiotensin II, which has a strong pressor effect, and also has the effect of inactivating bradykinin, which has a hypotensive effect. There is. Because of this action, angiotensin-converting enzyme inhibitors are used as therapeutic agents for hypertension and are known as commercially available drugs. Furthermore, angiotensin-converting enzyme inhibitors are used for many pathological conditions such as heart disease, kidney disease, cerebrovascular disorder, arteriosclerotic disease, diabetes, metabolic syndrome, and hypertension in the elderly.
これまでにアンジオテンシン変換酵素阻害作用を有するペプチドが天然物中から見出されている（特許文献１～３）。これらの文献には、牛由来カゼインから得られた特定構造のペプチドを有効成分とするアンジオテンシン変換酵素阻害剤について開示されている。特許文献１のペプチドのＩＣ５０（アンジオテンシン変換酵素の活性を５０％阻害するために必要な濃度）は７．７×１０-５Ｍであり、特許文献２のペプチドのＩＣ５０は１５．５μＭであることが開示されている。 Peptides having an angiotensin-converting enzyme inhibitory effect have been discovered from natural products (Patent Documents 1 to 3). These documents disclose angiotensin converting enzyme inhibitors containing a peptide with a specific structure obtained from bovine casein as an active ingredient. The IC50 (concentration required to inhibit 50% of angiotensin converting enzyme activity) of the peptide of Patent Document 1 is 7.7× 10-5 M, and the IC50 of the peptide of Patent Document 2 is 15.5 μM. is disclosed.
上記のように乳カゼイン由来のアンジオテンシン変換酵素阻害作用を有するペプチドが知られているが、これらのペプチド類では、未だアンジオテンシン変換酵素阻害活性は不十分である。よって、天然物型で、一層高いアンジオテンシン変換酵素阻害活性を有するペプチドの取得と、その食品又は医薬等への応用が望まれているところである。
本発明は、高いアンジオテンシン変換酵素阻害活性を有する新規ペプチドの提供及び当該ペプチドを有効成分として含むアンジオテンシン変換酵素阻害剤及びアンジオテンシン変換酵素阻害用飲食品を提供することを課題とする。
As mentioned above, peptides derived from milk casein that have angiotensin converting enzyme inhibitory activity are known, but these peptides still have insufficient angiotensin converting enzyme inhibitory activity. Therefore, it is desired to obtain a natural product-type peptide having higher angiotensin-converting enzyme inhibitory activity and to apply the same to foods, medicines, and the like.
An object of the present invention is to provide a novel peptide having high angiotensin-converting enzyme inhibitory activity, and to provide an angiotensin-converting enzyme inhibitor and an angiotensin-converting enzyme-inhibiting food or drink containing the peptide as an active ingredient.
本発明者らは、前記課題を解決するために鋭意検討を行った。すなわち、構造生物学的手法により、アンジオテンシン変換酵素の基質認識部位に強く結合するペプチドを探索した。その結果、従来より高いアンジオテンシン変換酵素阻害活性を有する新規なペプチドを発見し、本発明を完成するに至った。 The present inventors conducted extensive studies to solve the above problems. Specifically, using structural biology techniques, we searched for peptides that strongly bind to the substrate recognition site of angiotensin-converting enzyme. As a result, a novel peptide having higher angiotensin-converting enzyme inhibitory activity than conventional peptides was discovered, and the present invention was completed.
すなわち、本発明は、以下の構成を有する。
（１）下記のアミノ酸配列からなるペプチド。
Trp-Ile-Asp
（２）下記のアミノ酸配列を有効成分として含有するアンジオテンシン変換酵素阻害剤。
Trp-Ile-Asp
（３）下記のアミノ酸配列からなるペプチドを有効成分として含有するアンジオテンシン変換酵素阻害用飲食品。
Trp-Ile-Asp
That is, the present invention has the following configuration.
(1) A peptide consisting of the following amino acid sequence.
Trp-Ile-Asp
(2) An angiotensin converting enzyme inhibitor containing the following amino acid sequence as an active ingredient.
Trp-Ile-Asp
(3) A food or drink product for inhibiting angiotensin converting enzyme containing a peptide having the following amino acid sequence as an active ingredient.
Trp-Ile-Asp
本発明の好ましい実施形態について詳細に説明する。ただし、本発明は以下の好ましい実施形態に限定されず、本発明の範囲内で自由に変更することができるものである 。
尚、本明細書において百分率は特に断りのない限り質量による表示である。
A preferred embodiment of the present invention will be described in detail. However, the present invention is not limited to the following preferred embodiments, and can be freely modified within the scope of the present invention.
In this specification, percentages are expressed by mass unless otherwise specified.
（Ｔｒｐ－Ｉｌｅ－Ａｓｐで表される配列を有するペプチド）
本発明のペプチドは、Ｔｒｐ－Ｉｌｅ－Ａｓｐで表される配列を有する。本発明において、ＴｒｐはＬ－トリプトファン残基、ＩｌｅはＬ－イソロイシン残基、ＡｓｐはＬ－アスパラギン酸残基を示す。また、本発明のペプチドは、このペプチドの製剤学上許容されうる酸付加塩および塩基付加塩等であってもよい。酸付加塩としては、例えば、塩酸、硫酸、硝酸、リン酸等の無機酸との塩；ギ酸、酢酸、プロピオン酸、グリコール酸、コハク酸、リンゴ酸、酒石酸、クエン酸等の有機酸との塩等が挙げられる。また、製剤学上許容されうる塩基付加塩としては、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩等のアルカリ土類金属塩；アンモニウム、エタノールアミン、トリエチルアミン、ジシクロヘキシルアミン等のアミン類との塩等がある。
(Peptide having a sequence represented by Trp-Ile-Asp)
The peptide of the present invention has a sequence represented by Trp-Ile-Asp. In the present invention, Trp represents an L-tryptophan residue, He represents an L-isoleucine residue, and Asp represents an L-aspartic acid residue. Furthermore, the peptide of the present invention may be a pharmaceutically acceptable acid addition salt or base addition salt of the peptide. Examples of acid addition salts include salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; salts with organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, succinic acid, malic acid, tartaric acid, and citric acid. Examples include salt. Pharmaceutically acceptable base addition salts include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts; amines such as ammonium, ethanolamine, triethylamine, and dicyclohexylamine. There are salt, etc.
本発明のペプチドは、化学合成によって製造することができる。本発明のペプチドの化学合成は、オリゴペプチドの合成に通常用いられている液相法または固相法によって行うことができる。合成されたペプチドは、必要に応じて脱保護され、未反応試薬、副生物等を除去する。このようなペプチドの合成は、市販のペプチド合成装置を用いて行うことができる。上記合成物から、好ましくは本発明のペプチドを単離、精製する。ペプチドの精製は、通常、オリゴペプチドの精製に用いられているのと同様の手法、例えばイオン交換クロマトグラフィー、吸着クロマトグラフィー、逆相クロマトグラフィー、分配クロマトグラフィー、ゲル濾過クロマトグラフィー等の各種クロマトグラフィー、溶媒沈殿、塩析、２種の液相間での分配等の方法を適宜組み合わせることによって、行うことができる。本発明のペプチドの精製に際しては、目的物質を含む画分は、後述するアンジオテンシン変換酵素阻害作用を指標として決定することができ、それらの画分の活性成分は質量分析法又は／およびプロテインシーケンサーにより同定することができる。 The peptide of the present invention can be produced by chemical synthesis. Chemical synthesis of the peptide of the present invention can be carried out by a liquid phase method or a solid phase method commonly used for oligopeptide synthesis. The synthesized peptide is deprotected as necessary to remove unreacted reagents, by-products, and the like. Such peptide synthesis can be performed using a commercially available peptide synthesizer. The peptide of the present invention is preferably isolated and purified from the above-mentioned synthetic product. Purification of peptides is usually carried out using techniques similar to those used for purification of oligopeptides, such as ion exchange chromatography, adsorption chromatography, reversed phase chromatography, partition chromatography, gel filtration chromatography, etc. This can be carried out by appropriately combining methods such as , solvent precipitation, salting out, and distribution between two liquid phases. When purifying the peptide of the present invention, fractions containing the target substance can be determined using the angiotensin converting enzyme inhibitory effect described below as an indicator, and the active components of these fractions can be determined by mass spectrometry and/or protein sequencer. Can be identified.
また、本発明のペプチドは、同ペプチドをコードする組換えＤＮＡを適当な宿主細胞で 発現させることによっても、製造することができる。組換えＤＮＡの作成に必要なベクター、及び宿主は、通常タンパク質やペプチドの製造に用いられているものを使用することができる。
本発明のペプチドは、天然物を由来として抽出されたものであってもよく、天然物からアンジオテンシン変換酵素阻害作用を指標として抽出することができる。抽出された画分の精製度は、必要とされるアンジオテンシン変換酵素阻害活性の程度に応じて精製すればよい。したがって、高度に精製された本発明のペプチドだけではなく、本発明のペプチドを含む粗画分も本発明の有効成分としてのペプチドの範囲に含まれる。
Furthermore, the peptide of the present invention can also be produced by expressing a recombinant DNA encoding the peptide in an appropriate host cell. Vectors and hosts necessary for the production of recombinant DNA can be those commonly used in the production of proteins and peptides.
The peptide of the present invention may be extracted from natural products, and can be extracted from natural products using angiotensin converting enzyme inhibitory activity as an indicator. The degree of purification of the extracted fraction may be determined depending on the degree of angiotensin-converting enzyme inhibitory activity required. Therefore, not only the highly purified peptide of the present invention but also a crude fraction containing the peptide of the present invention is included within the scope of the peptide as an active ingredient of the present invention.
（アンジオテンシン変換酵素阻害剤）
本発明のアンジオテンシン変換酵素阻害剤は、前記Ｔｒｐ－Ｉｌｅ－Ａｓｐで表される配列からなるペプチドを有効成分として含む。本発明のアンジオテンシン変換酵素阻害剤は、飲食品、飼料、化粧品、医薬部外品、医薬品等が挙げられる。特に飲食品の場合をアンジオテンシン変換酵素阻害用飲食品、医薬品の場合をアンジオテンシン変換酵素阻害用医薬品ということがある。
(Angiotensin-converting enzyme inhibitor)
The angiotensin converting enzyme inhibitor of the present invention contains a peptide consisting of the sequence represented by Trp-Ile-Asp as an active ingredient. Examples of the angiotensin converting enzyme inhibitor of the present invention include food and drink products, feeds, cosmetics, quasi-drugs, and pharmaceuticals. In particular, food and drinks are sometimes referred to as foods and drinks for angiotensin converting enzyme inhibition, and pharmaceuticals are sometimes referred to as drugs for inhibiting angiotensin converting enzyme.
本発明のペプチドを有効成分とするアンジオテンシン変換酵素阻害剤は、経口投与、非経口投与のいずれによって投与されてもよい。非経口投与としては、経皮投与、静注、直腸投与、吸入等が挙げられる。本発明のペプチドを経口投与するに際しては、有効成分であるＴｒｐ－Ｉｌｅ－Ａｓｐをそのままの状態で投与することもできるが、常法に従い、飲食品に添加したり、粉末剤、顆粒剤、錠剤、カプセル剤、ドリンク剤等に製剤化して投与することもできる。 The angiotensin converting enzyme inhibitor containing the peptide of the present invention as an active ingredient may be administered either orally or parenterally. Examples of parenteral administration include transdermal administration, intravenous injection, rectal administration, and inhalation. When administering the peptide of the present invention orally, the active ingredient Trp-Ile-Asp can be administered as it is, but it can also be added to foods and drinks, powdered, granulated, or tableted according to conventional methods. It can also be formulated into capsules, drinks, etc. and administered.
（アンジオテンシン変換酵素阻害用飲食品）
本発明のアンジオテンシン変換酵素阻害用飲食品は、前記Ｔｒｐ－Ｉｌｅ－Ａｓｐで表される配列からなるペプチドを有効成分として含む。このような食品は、特に、特定保健用食品・飲食品、機能性表示食品・飲食品、栄養補助食品・飲食品と呼ばれることがある。これらの飲食品は、液状、ペースト状、固体、粉末等の形態を問わず、錠菓、流動食等のほか、例えば、チーズ、発酵乳などの乳製品、ゼリーなどの菓子類、ソーセージなどの練製品、うどんやそばなどの麺類、果汁飲料、乳飲料等の飲食品が挙げられる。
(Food and drink for angiotensin converting enzyme inhibition)
The food or drink product for inhibiting angiotensin converting enzyme of the present invention contains a peptide having the sequence represented by Trp-Ile-Asp as an active ingredient. Such foods are sometimes referred to as foods/drinks for specified health uses, foods/drinks with functional claims, and nutritional supplements/drinks. These food and drink products include tablets, liquid foods, etc., regardless of their form such as liquid, paste, solid, powder, etc., as well as dairy products such as cheese and fermented milk, confectionery such as jelly, sausages, etc. Examples include food and drink products such as paste products, noodles such as udon and soba, fruit juice drinks, and milk drinks.
（アンジオテンシン変換酵素阻害用医薬品）
本発明のアンジオテンシン変換酵素阻害用医薬品は、前記Ｔｒｐ－Ｉｌｅ－Ａｓｐで表される配列からなるペプチドを有効成分として含む。医薬の製剤化にあたっては、担体、賦形剤、結合剤、崩壊剤、滑沢剤、着色剤、安定剤、希釈剤、注射剤用溶剤等の添加剤を使用できる。具体的製剤として、錠剤、散剤、カプセル剤、顆粒剤、丸剤、トローチ剤、等を例示することができる。
本発明において、粉末剤、顆粒剤、錠剤、カプセル剤等の経口剤は、例えば、澱粉、乳糖、白糖、マンニット、カルボキシメチルセルロース、コーンスターチ、無機塩類等の賦形剤を用いて常法によって製剤化することが可能である。この種の製剤には、前記賦形剤の他に、結合剤、崩壊剤、界面活性剤、滑沢剤、流動性促進剤、着色料、香料等を適宜使用してもよい。
(Medicine for angiotensin-converting enzyme inhibition)
The pharmaceutical for inhibiting angiotensin converting enzyme of the present invention contains a peptide consisting of the sequence represented by Trp-Ile-Asp as an active ingredient. In formulating pharmaceuticals, additives such as carriers, excipients, binders, disintegrants, lubricants, colorants, stabilizers, diluents, and injection solvents can be used. Specific formulations include tablets, powders, capsules, granules, pills, troches, and the like.
In the present invention, oral preparations such as powders, granules, tablets, and capsules are prepared by conventional methods using excipients such as starch, lactose, sucrose, mannitol, carboxymethyl cellulose, corn starch, and inorganic salts. It is possible to convert In addition to the excipients mentioned above, binders, disintegrants, surfactants, lubricants, fluidity promoters, colorants, fragrances, and the like may be used as appropriate in this type of preparation.
結合剤としては、例えば、澱粉、デキストリン、アラビアガム、ゼラチン、ヒドロキシプロピルスターチ、カルボキシメチルセルロースナトリウム、メチルセルロース、結晶性セルロース、エチルセルロース、ポリビニルピロリドンが挙げられ、崩壊剤としては、例えば、澱粉、ヒドロキシプロピルスターチ、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、架橋カルボキシメチルセルロースナトリウム、結晶性セルロース等が挙げられる。また、界面活性剤としては、大豆レシチン、蔗糖脂肪酸エステル等、滑沢剤としては、タルク、ロウ、蔗糖脂肪酸エステル、水素添加植物油等、流動性促進剤としては無水ケイ酸、乾燥水酸化アルミニウム、ケイ酸マグネシウム等が挙げられる。 Examples of binders include starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, sodium carboxymethyl cellulose, methyl cellulose, crystalline cellulose, ethyl cellulose, and polyvinylpyrrolidone, and examples of disintegrants include starch, hydroxypropyl starch. , carboxymethylcellulose, sodium carboxymethylcellulose, crosslinked sodium carboxymethylcellulose, crystalline cellulose, and the like. In addition, surfactants include soybean lecithin, sucrose fatty acid ester, etc., lubricants include talc, wax, sucrose fatty acid ester, hydrogenated vegetable oil, etc., and fluidity promoters include silicic anhydride, dried aluminum hydroxide, Examples include magnesium silicate.
（その他の用途）
本発明のペプチドを有効成分として飼料（ペット用を含む）に含有させ、アンジオテンシン変換酵素阻害作用を有する飼料として加工することもできる。
また、本発明のペプチドを有効成分として化粧品や医薬部外品に含有させ、アンジオテンシン変換酵素阻害作用を有する化粧品や医薬部外品として加工することもできる。
(Other uses)
It is also possible to incorporate the peptide of the present invention as an active ingredient into feed (including for pets) and process it as feed having an angiotensin-converting enzyme inhibitory effect.
Furthermore, the peptide of the present invention can be incorporated as an active ingredient into cosmetics or quasi-drugs, and processed into cosmetics or quasi-drugs having angiotensin-converting enzyme inhibiting action.
本発明のアンジオテンシン変換酵素阻害剤（飲食品、医薬品、その他の用途の各態様）において、本発明のペプチドの配合量は、アンジオテンシン変換酵素阻害剤の最終組成物に対して、０．００１％質量以上であることが好ましい。 In the angiotensin converting enzyme inhibitor of the present invention (for food/beverage products, pharmaceuticals, and other applications), the amount of the peptide of the present invention is 0.001% by weight based on the final composition of the angiotensin converting enzyme inhibitor. It is preferable that it is above.
本発明のアンジオテンシン変換酵素阻害剤の投与量は、年齢、症状等により異なるが、通常、本発明のペプチドの量として０．００１ｍｇ～１０００ｍｇであり、１日１回、又は複数回に分けて投与してもよい。また、本発明のアンジオテンシン変換酵素阻害剤を摂取又は服用する場合は、食前、食間、食後のいずれのタイミングであっても、本発明の効果は十分に発揮されるものである。 The dosage of the angiotensin-converting enzyme inhibitor of the present invention varies depending on age, symptoms, etc., but is usually 0.001 mg to 1000 mg of the peptide of the present invention, administered once a day or divided into multiple doses. You may. Furthermore, when the angiotensin-converting enzyme inhibitor of the present invention is ingested or administered, the effects of the present invention are fully exhibited regardless of whether it is taken before meals, between meals, or after meals.
以下に実施例を用いて本発明をさらに詳しく説明するが、本発明はこれら実施例に限定されるものではない。 The present invention will be explained in more detail below using Examples, but the present invention is not limited to these Examples.
＜実施例１＞
［ペプチドのアンジオテンシン変換酵素阻害作用］
（１）試験方法
（１－１）アンジオテンシン変換酵素阻害の測定
アンジオテンシン変換酵素阻害の測定は、カッシュマンらの方法〔バイオケミカル・ファーマコロジー２０巻、１６３７～１６４８頁（１９７１）〕に準じて行った。
試料として、化学合成した本発明のペプチドTrp-Ile-Asp (ジーエルバイオケム社)を用いた。
<Example 1>
[Angiotensin converting enzyme inhibitory effect of peptide]
(1) Test method (1-1) Measurement of angiotensin converting enzyme inhibition Measurement of angiotensin converting enzyme inhibition was carried out according to the method of Cushman et al. [Biochemical Pharmacology Vol. 20, pp. 1637-1648 (1971)]. Ta.
As a sample, the chemically synthesized peptide Trp-Ile-Asp (GL Biochem) of the present invention was used.
（ｉ）試料を０．１Ｍホウ酸緩衝液（０．３Ｍ ＮａＣｌを含む、ｐＨ８．３）に溶解し、試験管に０．０８ｍｌ入れた後、０．１Ｍホウ酸緩衝液（０．３Ｍ ＮａＣｌを含む、ｐＨ ８．３）で５ｍＭに調製した酵素基質（ヒプリルヒスチジルロイシン、シグマ社製）０．２ｍｌを添加し、３７℃で３分間保温した。次いで、蒸留水を添加して０．１Ｕ／ｍｌになるように調製したウサギ肺のアンジオテンシン変換酵素（シグマ社製）０．０２ｍｌを添加し、３７℃で３０分間反応させた。 (i) Dissolve the sample in 0.1M borate buffer (containing 0.3M NaCl, pH 8.3), add 0.08ml to a test tube, and then add 0.1M borate buffer (0.3M NaCl) to the test tube. 0.2 ml of an enzyme substrate (hypril histidyl leucine, manufactured by Sigma) prepared to 5mM with (pH 8.3) was added, and the mixture was incubated at 37°C for 3 minutes. Next, 0.02 ml of rabbit lung angiotensin converting enzyme (manufactured by Sigma), which had been adjusted to 0.1 U/ml by adding distilled water, was added and reacted at 37° C. for 30 minutes.
(ii)その後、１Ｎ塩酸０．２５ｍｌを添加して反応を終了した後、１．７ｍｌの酢酸エチルを加え、２０秒間激しく攪件し、３０００ｒｐｍで１０分間遠心分離して、酢酸エチル層を１．４ｍｌ採取した。得られた酢酸エチル層を加熱して溶媒を除去した後、蒸留水を１ ．０ｍｌ添加し、抽出した馬尿酸の吸収（２２８ｎｍの吸光度）を測定して、これを酵素活性とした。 (ii) Then, after terminating the reaction by adding 0.25 ml of 1N hydrochloric acid, 1.7 ml of ethyl acetate was added, stirred vigorously for 20 seconds, and centrifuged at 3000 rpm for 10 minutes to separate the ethyl acetate layer. .4 ml was collected. After heating the obtained ethyl acetate layer to remove the solvent, 1. 0 ml was added, and the absorption (absorbance at 228 nm) of the extracted hippuric acid was measured, and this was taken as the enzyme activity.
（１－２）ＩＣ５０決定方法
次の式から、阻害活性を求め、縦軸に阻害率、横軸に試料濃度をプロットして阻害曲線の式を求めた後、ＩＣ５０［アンジオテンシン変換酵素の活性を５０％阻害するために必要な試料濃度（μＭ）］を決定した。
(1-2) Method for determining IC 50 Determine the inhibitory activity from the following formula, plot the inhibition rate on the vertical axis and the sample concentration on the horizontal axis to determine the formula for the inhibition curve, and then calculate the IC 50 [of angiotensin converting enzyme]. The sample concentration (μM) required to inhibit the activity by 50%] was determined.
阻害率（％）＝（Ａ－Ｂ）／（Ａ－Ｃ）×１００
Ａ：試料（ペプチド）を含まない場合の酵素活性（２２８ｎｍの吸光度）
Ｂ：試料を添加した場合の酵素活性（２２８ｎｍの吸光度）
Ｃ：酵素および試料を添加しない場合の酵素活性（２２８ｎｍの吸光度）
Inhibition rate (%) = (A-B)/(A-C) x 100
A: Enzyme activity (absorbance at 228 nm) without sample (peptide)
B: Enzyme activity when sample is added (absorbance at 228 nm)
C: Enzyme activity when no enzyme or sample is added (absorbance at 228 nm)
（２）試験結果
本試験結果を表１、図１、図２、図３及び表２に示す。
表１、図１より、阻害率５０％のときの試料（本発明ペプチド）の濃度ＩＣ５０は、０．６μＭであった（表２）。
図２はＴｒｐ－Ｉｌｅ－Ａｓｐを４００μＭで添加した上記(i)の反応液のクロマトグラムであり、図３は添加していない反応液のクロマトグラムである。図２は、基質のヒプリルヒスチジルロイシンが馬尿酸に分解されず、アンジオテンシン変換酵素の機能を阻害していることを示している。また、図３は、アンジオテンシン変換酵素の作用により基質のヒプリルヒスチジルロイシンが馬尿酸に分解されたことを示している。
したがって、本発明のＴｒｐ－Ｉｌｅ－Ａｓｐの配列からなるペプチドは強力なアンジオテンシン変換酵素阻害活性を有することが判明した。
(2) Test results The test results are shown in Table 1, FIG. 1, FIG. 2, FIG. 3, and Table 2.
From Table 1 and FIG. 1, the concentration IC 50 of the sample (peptide of the present invention) when the inhibition rate was 50% was 0.6 μM (Table 2).
FIG. 2 is a chromatogram of the reaction solution of (i) above to which Trp-Ile-Asp was added at 400 μM, and FIG. 3 is a chromatogram of the reaction solution to which Trp-Ile-Asp was not added. FIG. 2 shows that the substrate hipryl histidyl leucine is not decomposed into hippuric acid and inhibits the function of angiotensin converting enzyme. Furthermore, FIG. 3 shows that the substrate hipryl histidyl leucine was decomposed into hippuric acid by the action of angiotensin converting enzyme.
Therefore, it was found that the peptide consisting of the Trp-Ile-Asp sequence of the present invention has a strong angiotensin-converting enzyme inhibitory activity.
本発明によれば、高いアンジオテンシン変換酵素阻害活性を有する新規なペプチドが提供される。同ペプチドを有効成分として含有するアンジオテンシン変換酵素阻害剤は、医薬品として利用することができる。また、同ペプチドは、すべて天然型（Ｌ体）のアミノ酸から構成されるため、安全性が高くアンジオテンシン変換酵素阻害用飲食品としても用いることができる。 According to the present invention, a novel peptide having high angiotensin-converting enzyme inhibitory activity is provided. Angiotensin converting enzyme inhibitors containing the same peptide as an active ingredient can be used as pharmaceuticals. Furthermore, since the peptide is composed entirely of natural (L-form) amino acids, it is highly safe and can be used as a food or drink for inhibiting angiotensin converting enzyme.
Claims (3)
Trp-Ile-Asp A peptide consisting of the amino acid sequence below.
Trp-Ile-Asp
Trp-Ile-Asp An angiotensin converting enzyme inhibitor containing the following amino acid sequence as an active ingredient.
Trp-Ile-Asp
Trp-Ile-Asp
A food/beverage product for inhibiting angiotensin converting enzyme containing a peptide having the following amino acid sequence as an active ingredient.
Trp-Ile-Asp
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