US20070122451A1 - Biogically non-degradable peptides, angiostensin converting enzyme inhibitor, drug and functional food - Google Patents

Biogically non-degradable peptides, angiostensin converting enzyme inhibitor, drug and functional food Download PDF

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Publication number
US20070122451A1
US20070122451A1 US10/566,057 US56605704A US2007122451A1 US 20070122451 A1 US20070122451 A1 US 20070122451A1 US 56605704 A US56605704 A US 56605704A US 2007122451 A1 US2007122451 A1 US 2007122451A1
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United States
Prior art keywords
pro
peptides
living organism
present
ace
Prior art date
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Abandoned
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US10/566,057
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English (en)
Inventor
Naoyuki Yamamoto
Seiichi Mizuno
Shingo Nishimura
Hideo Nishimura
Takanobu Gotou
Keiichi Matsuura
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Asahi Soft Drinks Co Ltd
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Calpis Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
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Assigned to CALPIS CO., LTD. reassignment CALPIS CO., LTD. CORRECTIVE ASSIGNMENT: PLEASE CORRECT THE SERIAL NUMBER PREVIOUSLY RECORDED 4/16/2007 R/F 019163/0494 Assignors: GOTOU, TAKANOBU, MATSUURA, KEIICHI, MIZUNO, SEIICHI, NISHIMURA, HIDEO FOR NISHIMURA, SHINGO (DECEASED), YAMAMOTO, NAOYUKI
Publication of US20070122451A1 publication Critical patent/US20070122451A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/18—Peptides; Protein hydrolysates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06086—Dipeptides with the first amino acid being basic
    • C07K5/06095—Arg-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to novel in vivo indigestible peptides that are highly absorbable and hardly digestible in living organism when administered orally or through other route, and to angiotensin converting enzyme inhibitors containing the peptides as active ingredients, and medicine and functional foods, such as foods for specified health use, containing the inhibitor and having hypotensive effect.
  • ACE angiotensin converting enzyme
  • ACE converts a precursor, angiotensin I, to angiotensin II having vasoconstrictive activity in living organism, to thereby raise the blood pressure.
  • peptides having ACE inhibitory activity are expected to exhibit hypotensive effect by inhibiting ACE to suppress production of angiotensin II in living organism.
  • Such peptides having ACE inhibitory activity have been reported in many publications including the following Patent Publications 1 to 3.
  • Patent Publication 4 teaches that low molecular weight peptides mainly composed of dipeptides and tripeptides and having an average chain length of not longer than 3, have excellent intestinal absorbability. However, it is not known in detail which peptides contribute to enhancement of the in vivo digestion resistance.
  • peptides are desired that have high absorbability and digestion resistance in living organism, and are capable of effectively exhibiting useful functions, such as ACE inhibitory activity, in living organism.
  • Patent Publication 1 JP-2-62828-A
  • Patent Publication 2 JP-3-120225-A
  • Patent Publication 3 JP-6-40944-A
  • Patent Publication 4 JP-5-252979-A
  • the present inventors have made intensive researches to find out that, among dipeptides and tripeptides having good in vivo absorbability, peptides having dipeptide Xaa-Pro or tripeptide Xaa-Pro-Pro sequences (Xaa may be any amino acid) with Pro at the carboxyl terminals, are indigestible in living organism, and capable of effectively exhibiting their functions in living organism.
  • the inventors have also found out that, among the dipeptides and tripeptides having such sequences, those having particular sequences are particularly excellent in ACE inhibitory activity or the like properties, to thereby complete the present invention.
  • an in vivo indigestible peptide having Pro at a carboxyl terminal selected from the group consisting of Ile-Pro, Glu-Pro, Arg-Pro, Gln-Pro, Met-Pro, and Ser-Pro-Pro.
  • an ACE inhibitor comprising as active ingredients in vivo indigestible peptides having Pro at carboxyl terminals, consisting at least one of Ile-Pro, Glu-Pro, Arg-Pro, Gln-Pro, Met-Pro, and Ser-Pro-Pro, or a salt thereof.
  • a medicine or functional food having hypotensive effect comprising the ACE inhibitor.
  • ACE inhibitor in the manufacture of functional food or medicine having hypotensive effect.
  • the in vivo indigestible peptides of the present invention are dipeptides or tripeptides of particular sequences with Pro at the carboxyl terminals, the present peptides are highly absorbable and hardly digestible in living organism, and expected to effectively exhibit functions, such as hypotensive effect, in living organism.
  • the ACE inhibitor of the present invention contains the above in vivo indigestible peptides as active ingredients, the present inhibitor is expected to effectively exhibit ACE inhibitory activity in living organism.
  • the medicine and functional food of the present invention contain the ACE inhibitor, the present medicine and functional food are expected to effectively exhibit hypotensive effect in living organism.
  • FIG. 1 is a graph showing the results of evaluation of in vivo absorbability and digestion resistance of Xaa-Pro and Xaa-Pro-Pro performed in Referential Example 1.
  • the in vivo indigestible peptide of the present invention is a dipeptide or tripeptide having Pro at the carboxyl terminal, consisting at least one of Ile-Pro, Glu-Pro, Arg-Pro, Gln-Pro, Met-Pro, and Ser-Pro-Pro.
  • the in vivo indigestible peptide means a dipeptide Xaa-Pro or a tripeptide Xaa-Pro-Pro having Pro at the carboxyl terminal, which has high digestion resistance against in vivo peptidases when absorbed intestinally in living organism.
  • the in vivo indigestible peptide of the present invention may be prepared, for example, from the corresponding amino acids by ordinary organic synthesis or the like method.
  • the present peptide may also be prepared, for example, by digesting food protein, such as animal milk casein, through fermentation with lactic acid bacteria, followed by purification; or by hydrolyzing food protein through an enzymatic method with an appropriate combination of proteinases and peptidases, followed by purification.
  • the purification does not have to result in isolation of the dipeptide or tripeptide, and may be concentration and purification by a suitable combination of conventional purification methods for increasing the peptide concentration.
  • the animal milk casein may be, for example, casein from cow's milk, horse's milk, goat's milk, and sheep's milk, with cow's milk casein being particularly preferred.
  • the ACE inhibitor of the present invention contains, as active ingredients, in vivo indigestible peptides having Pro at the carboxyl terminals, consisting at least one of Ile-Pro, Glu-Pro, Arg-Pro, Gln-Pro, Met-Pro, and Ser-Pro-Pro, i.e., the in vivo indigestible peptides of the present invention, or a salt thereof.
  • the peptide salt is preferably a pharmaceutically acceptable salt, such as salts of inorganic acid including hydrochloride, sulfate, or phosphate, or of organic acid including acetate, trifluoroacetate, citrate, maleate, fumarate, lactate, or tartrate.
  • a pharmaceutically acceptable salt such as salts of inorganic acid including hydrochloride, sulfate, or phosphate, or of organic acid including acetate, trifluoroacetate, citrate, maleate, fumarate, lactate, or tartrate.
  • the ACE inhibitor of the present invention may optionally contain various auxiliary additives for improving the nutritional balance or flavor.
  • auxiliary additives may include various carbohydrates, lipids, vitamins, minerals, sweeteners, flavoring agents, pigments, and texture improvers.
  • the amount of the ACE inhibitor for use may suitably be selected depending on the kinds of peptides and salts thereof contained as active ingredients, and is not particularly limited.
  • the amount of the inhibitor in terms of peptides may preferably be about 0.01 to 100 mg/kg per ingestion, with no particular upper limit.
  • the ACE inhibitor of the present invention may be formulated with a pharmaceutically acceptable carrier into various dosage forms in accordance with conventional methods.
  • the present inhibitor may be mixed with a vehicle, and optionally a binder, disintegrator, lubricant, coloring agent, taste corrigent, flavor corrigent, or the like as desired, and formulated into tablets, coated tablets, granules, powders, capsules, or the like.
  • Such medicine may optionally contain other components such as peptides having ACE inhibitory activity or hypotensive effect other than the active ingredients of the present ACE inhibitor.
  • the ACE inhibitor of the present invention may be used by mixing in functional food such as foods for specified health use claiming hypotensive effect.
  • functional food such as foods for specified health use claiming hypotensive effect.
  • functional food may include beverages, yogurt, liquid food, jelly, candies, retort food, tablet candies, cookies, sponge cakes, bread, biscuits, and chocolates.
  • the inhibitor may also be formulated into capsules or tablets for use as dietary supplements.
  • peptides having the sequence Xaa-Pro or Xaa-Pro-Pro present in casein derived from cow's milk Ile-Pro, Glu-Pro, Arg-Pro, Gln-Pro, Met-Pro, and Ser-Pro-Pro were chemically synthesized (manufactured by TORAY RESEARCH CENTER, INC., not lower than 95% purity). Solutions of each of these peptides at various concentrations were prepared, and measured for the ACE inhibitory activity in accordance with the method discussed below. The peptide concentration ( ⁇ M) at which the ACE inhibitory effect was 50% was taken as IC50 value. The results are shown in Table 1.
  • ACE derived from bovine lung (manufactured by WAKO PURE CHEMICAL INDUSTRIES, LTD.) was dissolved in a 0.1M borate buffer at pH 8.3 in an amount of 0.1 U, to obtain an ACE solution.
  • 80 ⁇ l of a diluted solution prepared by properly diluting a 5 mg/ml solution of each peptide shown in Table 1 with distilled water according to the IC50 value of that peptide 200 ⁇ l of a 5 mM hippuryl-histidyl-leucine (manufactured by SIGMA) solution containing 300 mM NaCl, and 20 ⁇ l of the ACE solution prepared above were introduced into a tube, and reacted at 37° C. for 30 minutes.
  • reaction was terminated by adding 250 ⁇ l of 1N hydrochloric acid (manufactured by WAKO PURE CHEMICAL INDUSTRIES, LTD.).
  • 1.7 ml of ethyl acetate (manufactured by WAKO PURE CHEMICAL INDUSTRIES, LTD.) was then added, and stirred.
  • 1.4 ml of the ethyl acetate layer was taken, placed in another tube, and evaporated at 120° C. for about 60 minutes to obtain a dried product.
  • the dried product was dissolved in 1 ml of distilled water, and the absorbance at 228 nm of hippuric acid extracted with ethyl acetate was measured.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Food Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Polymers & Plastics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
US10/566,057 2003-08-01 2004-07-30 Biogically non-degradable peptides, angiostensin converting enzyme inhibitor, drug and functional food Abandoned US20070122451A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2003285007 2003-08-01
JP2003-285007 2003-08-01
PCT/JP2004/010929 WO2005012334A1 (ja) 2003-08-01 2004-07-30 生体内非分解性ペプチド、アンジオテンシン変換酵素阻害剤、医薬及び機能性食品

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US20070122451A1 true US20070122451A1 (en) 2007-05-31

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US10/566,057 Abandoned US20070122451A1 (en) 2003-08-01 2004-07-30 Biogically non-degradable peptides, angiostensin converting enzyme inhibitor, drug and functional food
US10/565,497 Abandoned US20070299014A1 (en) 2003-08-01 2004-07-30 Casein hydrolyzate, process for producing the same and use thereof
US12/873,500 Active 2024-12-02 US8580557B2 (en) 2003-08-01 2010-09-01 Casein hydrolyzate, process for producing the same and use thereof

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US10/565,497 Abandoned US20070299014A1 (en) 2003-08-01 2004-07-30 Casein hydrolyzate, process for producing the same and use thereof
US12/873,500 Active 2024-12-02 US8580557B2 (en) 2003-08-01 2010-09-01 Casein hydrolyzate, process for producing the same and use thereof

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US (3) US20070122451A1 (ja)
EP (2) EP1669463B1 (ja)
JP (3) JP5341300B2 (ja)
KR (3) KR101115560B1 (ja)
CN (3) CN100439393C (ja)
AT (2) ATE442855T1 (ja)
AU (2) AU2004261522B2 (ja)
BR (2) BRPI0413242A (ja)
CA (2) CA2532537A1 (ja)
DE (2) DE602004017202D1 (ja)
DK (2) DK1669463T3 (ja)
EA (2) EA011570B1 (ja)
ES (2) ES2331312T3 (ja)
HK (2) HK1094008A1 (ja)
MX (2) MXPA06000878A (ja)
NO (2) NO20060994L (ja)
NZ (2) NZ545340A (ja)
PL (1) PL1669463T3 (ja)
PT (2) PT1661909E (ja)
TW (2) TWI349676B (ja)
UA (2) UA87278C2 (ja)
WO (2) WO2005012542A1 (ja)
ZA (2) ZA200601739B (ja)

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WO2007013426A1 (ja) 2005-07-26 2007-02-01 Calpis Co., Ltd. 発酵乳の製造方法及び発酵乳飲食品
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JP5750039B2 (ja) * 2008-03-26 2015-07-15 グランビア ニュートリショナルズ （アイルランド） リミテッド ロイシンリッチペプチド組成物および単離法
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CN101570568B (zh) * 2009-06-15 2012-05-30 东北农业大学 一种发酵乳中的ace抑制肽及其制备方法
CN102187935B (zh) * 2010-03-19 2012-12-19 江南大学 一种制备酪蛋白磷酸肽与ace抑制肽的方法
CN102399261B (zh) * 2010-09-07 2014-06-25 任发政 具有血管紧张素转化酶c-端选择性抑制活性的三肽及其应用和组合物
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JP5718741B2 (ja) * 2011-06-24 2015-05-13 カルピス株式会社 脳機能改善用ペプチドの酵素的製造方法
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JP6306197B2 (ja) 2013-10-04 2018-04-04 イノウェイ・カンパニー・リミテッド 動物性タンパク加水分解物、その製造方法及びその用途
FR3017536B1 (fr) * 2014-02-18 2017-05-26 Univ La Rochelle Compositions pour la prevention et/ou le traitement de pathologies liees a l'alpha-glucosidase
ES2544153B1 (es) * 2014-02-24 2016-06-06 Ntd Labs, S.L. Uso de un hidrolizado de caseína como agente antiviral
JP6251667B2 (ja) 2014-06-03 2017-12-20 アサヒカルピスウェルネス株式会社 錠剤型即放性製剤及びその製造方法
CN105693817B (zh) 2014-11-27 2020-06-05 西北大学 一类三肽化合物及其制备方法与应用
JP6005202B2 (ja) * 2015-03-19 2016-10-12 アサヒグループホールディングス株式会社 脳機能改善用ペプチドの酵素的製造方法
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CN108003231A (zh) * 2017-11-13 2018-05-08 江苏大学 一种降低小分子肽中游离氨基酸含量的方法
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JPWO2019208700A1 (ja) * 2018-04-26 2021-04-30 ゼリア新薬工業株式会社 ジペプチド及びこれを含有する医薬組成物
CN110467649A (zh) * 2019-09-12 2019-11-19 浙江省农业科学院 一种抑制血管紧张素转换酶活性的多肽qeip及其应用
CN113321719B (zh) * 2021-05-20 2022-03-18 澳优乳业（中国）有限公司 一种寡肽及其制备方法与应用
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