JPWO2003066672A1 - peptide - Google Patents

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JPWO2003066672A1
JPWO2003066672A1 JP2003566043A JP2003566043A JPWO2003066672A1 JP WO2003066672 A1 JPWO2003066672 A1 JP WO2003066672A1 JP 2003566043 A JP2003566043 A JP 2003566043A JP 2003566043 A JP2003566043 A JP 2003566043A JP WO2003066672 A1 JPWO2003066672 A1 JP WO2003066672A1
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peptide
amino acid
acid sequence
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坂本　賢二
賢二 坂本
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • 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
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
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    • C07—ORGANIC CHEMISTRY
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    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
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    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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Abstract

本発明は、特に医薬、食品として有用なペプチドを提供することを目的とする。そのためにとった手段は、特定のアミノ酸配列を有するインスリン産生促進効果、胃酸分泌抑制効果、成長ホルモン産生促進効果、血圧降下効果、脂肪蓄積抑制効果、アレルギー抑制効果、鎮痛効果及び中枢神経系機能促進効果を有するペプチドからなる。本発明のペプチドを用いれば前記機能を有する新規な医薬、食品等を得ることができる。The object of the present invention is to provide a peptide that is particularly useful as a pharmaceutical or food. The measures taken for this purpose were to promote the production of insulin having a specific amino acid sequence, the effect of inhibiting gastric acid secretion, the effect of promoting growth hormone production, the effect of lowering blood pressure, the effect of suppressing fat accumulation, the effect of suppressing allergy, the analgesic effect, and the promotion of central nervous system function. It consists of an effective peptide. If the peptide of this invention is used, the novel pharmaceutical, foodstuff, etc. which have the said function can be obtained.

Description

技術分野
本発明は、ペプチドに関する。さらに詳しくは、インスリン産生促進効果、胃酸分泌抑制効果、成長ホルモン産生促進効果、血圧降下効果、脂肪蓄積抑制効果、アレルギー抑制効果、鎮痛効果、中枢神経系機能促進効果を有するペプチドに関する。
背景技術
従来より、効能効果が優れ、副作用が起きる等の欠点がない医薬品の開発が求められている。一方、生体内には数多くの生理活性物質が存在し、生体の正常な生命活動の維持に密接に関与していることは周知の事実である。それらの生体内生理活性物質及び合成生理活性物質はそれ自身、新しい医薬、食品等としての可能性を有すると共に、新たな医薬、食品等を開発するための知見を提供するものでもある。
本発明の目的は、特に医薬、食品として有用なペプチドを提供することにある。
発明の開示
本願発明者は上記課題を解決するために鋭意研究を行った結果、特定のアミノ酸配列を有するペプチドが優れた生理活性を有し、特に医薬、食品として有用であることを見いだし、本発明を完成するに至った。
すなわち、本発明は、配列表の配列番号１で示されるアミノ酸配列を有するペプチド、或いは該アミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって、インスリン産生促進効果を有するペプチド、該ペプチドを有効成分とするペプチド、これらのペプチドからなるインスリン産生促進剤、及び前記ペプチドを有効成分として含有するインスリン産生促進剤のような医薬又は食品である。
また、本発明は、配列表の配列番号２で示されるアミノ酸配列を有するペプチド、或いは該アミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって、胃酸分泌抑制効果を有するペプチド、該ペプチドを有効成分とするペプチド、これらのペプチドからなる胃酸分泌抑制剤、及び前記ペプチドを有効成分として含有する胃酸分泌抑制剤のような医薬又は食品である。
また、本発明は、配列表の配列番号３で示されるアミノ酸配列を有するペプチド、或いは該アミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって、成長ホルモン産生促進効果を有するペプチド、該ペプチドを有効成分とするペプチド、これらのペプチドからなる成長ホルモン産生促進剤、及び前記ペプチドを有効成分として含有する成長ホルモン産生促進剤のような医薬又は食品である。
さらに、本発明は、配列表の配列番号４、５、６、７、８、９、１０、１１又は１２で示されるアミノ酸配列を有するペプチド、或いは該アミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって、血圧降下効果を有するペプチド、該ペプチドを有効成分とするペプチド、これらのペプチドからなる血圧降下剤、及び前記ペプチドを有効成分として含有する血圧降下剤のような医薬又は食品である。
また、本発明は、配列表の配列番号１３、１４、１５、１６、１７又は１８で示されるアミノ酸配列を有するペプチド、或いは該アミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって、脂肪蓄積抑制効果を有するペプチド、該ペプチドを有効成分とするペプチド、これらのペプチドからなる脂肪蓄積抑制剤、及び前記ペプチドを有効成分として含有する脂肪蓄積抑制剤のような医薬又は食品である。
また、本発明は、配列表の配列番号１９で示されるアミノ酸配列を有するペプチド、或いは該アミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって、アレルギー抑制効果を有するペプチド、該ペプチドを有効成分とするペプチド、これらのペプチドからなるアレルギー抑制剤、及び前記ペプチドを有効成分として含有するアレルギー抑制剤のような医薬又は食品である。
また、本発明は、配列番号２０、２１又は２２で示されるアミノ酸配列を有するペプチド、或いは該アミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって、血圧降下効果を有するペプチド、該ペプチドを有効成分とするペプチド、これらのペプチドからなる血圧降下剤、及び前記ペプチドを有効成分として含有する血圧降下剤のような医薬又は食品である。
また、本発明は、配列番号２３又は２４で示されるアミノ酸配列を有するペプチド、或いは該アミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって、鎮痛効果を有するペプチド、該ペプチドを有効成分とするペプチド、これらのペプチドからなる鎮痛剤、及び前記ペプチドを有効成分として含有する鎮痛剤のような医薬又は食品である。
さらに、本発明は、配列番号２５、２６、２７、２８、２９、３０、３１又は３２で示されるアミノ酸配列を有するペプチド、或いは該アミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって、中枢神経系機能促進効果を有するペプチド、該ペプチドを有効成分とするペプチド、これらのペプチドからなる中枢神経系機能促進剤、及び前記ペプチドを有効成分として含有する中枢神経系機能促進剤のような医薬又は食品である。
発明を実施するための最良の形態
本発明の第１の発明に係るペプチドは、配列表の配列番号１で示されるアミノ酸配列を有するペプチドである。該ペプチドは、インスリンの産生を促進する機能を有するのでインスリン産生促進剤として有用であり、医薬、食品等に応用される。例えば、本第１の発明に係る前記ペプチドを有効成分として配合してインスリン産生促進剤等の医薬、食品等に応用される。これらのうちの医薬としてのインスリン産生促進剤は、糖尿病の治療及び予防に用いることができ、糖尿病治療薬としての応用も本発明のインスリン産生促進剤の範ちゅうに含まれる。
なお、一般に、生理活性を有するペプチドが、そのアミノ酸配列のうち少数のアミノ酸配列が置換し若しくは欠失し、又は該アミノ酸配列に少数のアミノ酸配列が挿入され若しくは付加された場合であっても、その生理活性を維持する場合があることは当業者に広く知られているところである。従って、配列番号１に示されるアミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであってインスリン産生促進効果を有するペプチドも本発明の第１の発明に係るペプチドの範囲に含まれる。このようなペプチドのアミノ酸配列は、配列番号１で示すアミノ酸配列と７０％以上、さらに好ましくは９０％以上の相同性を有していることが好ましい。
前記第１の発明に係る医薬としてのインスリン産生促進剤は、静脈注射、皮下注射、筋肉内注射、経直腸投与等の非経口の経路で投与するか又は経口投与することが好ましい。また、投与量は、患者の状態や有効成分の分子量等に基づき適宜決定されるが、通常、非経口投与の場合には体重１ｋｇ、１日当たり０．０１ｍｇ〜１ｍｇ程度が好ましく、経口投与の場合には体重１ｋｇ、１日当たり０．１ｍｇ〜１０ｍｇ程度が好ましい。また、前記第１の発明に係るペプチドからなるインスリン産生促進剤は、常法により適宜製剤することができ、例えば、生理食塩水に３０ｍｇ／ｌ〜３０００ｍｇ／ｌの濃度範囲で溶解したものを用いることができる。また、経口投与の場合には、飲料に添加していわゆるドリンク剤とすることもできる。
本発明の第２の発明に係るペプチドは、配列表の配列番号２で示されるアミノ酸配列を有するペプチドである。該ペプチドは、胃酸の分泌を抑制する機能を有するので胃酸分泌抑制剤として有用であり、医薬、食品等に応用される。例えば、本第２の発明に係る前記ペプチドを有効成分として配合して胃酸分泌抑制剤等の医薬、食品等に応用される。これらのうちの医薬としての胃酸分泌抑制剤は、胃潰瘍及び十二指腸潰瘍の治療及び予防に用いることができ、胃腸薬としての応用も本発明の胃酸分泌抑制剤の範ちゅうに含まれる。
なお、インスリン産生促進剤の場合と同様、配列番号２に示されるアミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって胃酸分泌抑制効果を有するペプチドも本発明の第２の発明に係るペプチドの範囲に含まれる。このようなペプチドのアミノ酸配列は、配列番号２で示すアミノ酸配列と７０％以上、さらに好ましくは９０％以上の相同性を有していることが好ましい。
前記第２の発明に係る医薬としての胃酸分泌抑制剤は、静脈注射、皮下注射、筋肉内注射、経直腸投与等の非経口の経路で投与するか又は経口投与することが好ましい。また、投与量は、患者の状態や有効成分の分子量等に基づき適宜決定されるが、通常、非経口投与の場合には体重１ｋｇ、１日当たり０．０１ｍｇ〜１ｍｇ程度が好ましく、経口投与の場合には体重１ｋｇ、１日当たり０．１ｍｇ〜１０ｍｇ程度が好ましい。また、前記第２の発明に係るペプチドからなる胃酸分泌抑制剤は、常法により適宜製剤することができ、例えば、生理食塩水に３０ｍｇ／ｌ〜３０００ｍｇ／ｌの濃度範囲で溶解したものを用いることができる。また、経口投与の場合には、飲料に添加していわゆるドリンク剤とすることもできる。
本発明の第３の発明に係るペプチドは、配列表の配列番号３で示されるアミノ酸配列を有するペプチドである。該ペプチドは、成長ホルモンの産生を促進する機能を有するので成長ホルモン産生促進剤として有用であり、医薬、食品等に応用される。例えば、本第３の発明に係る前記ペプチドを有効成分として配合して成長ホルモン産生促進剤等の医薬、食品等に応用される。これらのうちの医薬としての成長ホルモン産生促進剤は、小人症の治療に用いることができる。
なお、インスリン産生促進剤の場合と同様、配列番号３に示されるアミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって成長ホルモン産生促進効果を有するペプチドも本発明の第３の発明に係るペプチドの範囲に含まれる。このようなペプチドのアミノ酸配列は、配列番号３で示すアミノ酸配列と７０％以上、さらに好ましくは９０％以上の相同性を有していることが好ましい。
前記第３の発明に係る医薬としての成長ホルモン産生促進剤は、静脈注射、皮下注射、筋肉内注射、経直腸投与等の非経口の経路で投与するか又は経口投与することが好ましい。また、投与量は、患者の状態や有効成分の分子量等に基づき適宜決定されるが、通常、非経口投与の場合には体重１ｋｇ、１日当たり０．０１ｍｇ〜１ｍｇ程度が好ましく、経口投与の場合には体重１ｋｇ、１日当たり０．１ｍｇ〜１０ｍｇ程度が好ましい。また、前記第３の発明に係るペプチドからなる成長ホルモン産生促進剤は、常法により適宜製剤することができ、例えば、生理食塩水に３０ｍｇ／ｌ〜３０００ｍｇ／ｌの濃度範囲で溶解したものを用いることができる。また、経口投与の場合には、飲料に添加していわゆるドリンク剤とすることもできる。
本発明の第４の発明に係るペプチドは、配列表の配列番号４、５、６、７、８、９、１０、１１又は１２で示されるアミノ酸配列を有するペプチドである。該ペプチドは、血圧を降下させる機能を有するので血圧降下剤として有用であり、医薬、食品等に応用される。例えば、本第４の発明に係る前記ペプチドを有効成分として配合して血圧降下剤等の医薬、食品等に応用される。これらのうちの医薬としての血圧降下剤は、高血圧症の治療及び予防に用いることができ、高血圧症治療薬としての応用も本発明の血圧降下剤の範ちゅうに含まれる。
なお、インスリン産生促進剤の場合と同様、配列番号４、５、６、７、８、９、１０、１１又は１２に示されるアミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって血圧降下効果を有するペプチドも本発明の第４の発明に係るペプチドの範囲に含まれる。このようなペプチドのアミノ酸配列は、配列番号４、５、６、７、８、９、１０、１１又は１２で示すアミノ酸配列と７０％以上、さらに好ましくは９０％以上の相同性を有していることが好ましい。
前記第４の発明に係る医薬としての血圧降下剤は、静脈注射、皮下注射、筋肉内注射、経直腸投与等の非経口の経路で投与するか又は経口投与することが好ましい。また、投与量は、患者の状態や有効成分の分子量等に基づき適宜決定されるが、通常、非経口投与の場合には体重１ｋｇ、１日当たり０．０１ｍｇ〜１ｍｇ程度が好ましく、経口投与の場合には体重１ｋｇ、１日当たり０．１ｍｇ〜１０ｍｇ程度が好ましい。また、前記第４の発明に係るペプチドからなる血圧降下剤は、常法により適宜製剤することができ、例えば、生理食塩水に３０ｍｇ／ｌ〜３０００ｍｇ／ｌの濃度範囲で溶解したものを用いることができる。また、経口投与の場合には、飲料に添加していわゆるドリンク剤とすることもできる。
本発明の第５の発明に係るペプチドは、配列表の配列番号１３、１４、１５、１６、１７又は１８で示されるアミノ酸配列を有するペプチドである。該ペプチドは、脂肪の蓄積を抑制する機能（脂肪蓄積抑制効果）を有するので脂肪蓄積抑制剤として有用であり、医薬、食品等に応用される。例えば、本第５の発明に係る前記ペプチドを有効成分として配合して脂肪蓄積抑制剤等の医薬、食品等に応用される。これらのうちの医薬としての脂肪蓄積抑制剤は、高脂血症の治療及び予防等に用いることができ、高脂血症用剤、肥満治療剤、肥満予防剤としての応用も本発明の脂肪蓄積抑制剤の範ちゅうに含まれる。
なお、一般に、生理活性を有するペプチドが、そのアミノ酸配列のうち少数のアミノ酸配列が置換し若しくは欠失し、又は該アミノ酸配列に少数のアミノ酸配列が挿入され若しくは付加された場合であっても、その生理活性を維持する場合があることは当業者に広く知られているところである。従って、配列番号１３、１４、１５、１６、１７又は１８に示されるアミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって脂肪蓄積抑制効果を有するペプチドも本発明の第５の発明に係るペプチドの範囲に含まれる。このようなペプチドのアミノ酸配列は、配列番号１３、１４、１５、１６、１７又は１８で示すアミノ酸配列と７０％以上、さらに好ましくは９０％以上の相同性を有していることが好ましい。
前記第５の発明に係る医薬としての脂肪蓄積抑制剤は、静脈注射、皮下注射、筋肉内注射、経直腸投与等の非経口の経路で投与するか又は経口投与することが好ましい。また、投与量は、患者の状態や有効成分の分子量等に基づき適宜決定されるが、通常、非経口投与の場合には体重１ｋｇ、１日当たり０．０１ｍｇ〜１ｍｇ程度が好ましく、経口投与の場合には体重１ｋｇ、１日当たり０．１ｍｇ〜１０ｍｇ程度が好ましい。また、前記第５の発明に係るペプチドからなる脂肪蓄積抑制剤は、常法により適宜製剤化することができ、例えば、生理食塩水に３０ｍｇ／ｌ〜３０００ｍｇ／ｌの濃度範囲で溶解したものを用いることができる。また、経口投与の場合には、飲料に添加していわゆるドリンク剤とすることもできる。
本発明の第６の発明に係るペプチドは、配列表の配列番号１９で示されるアミノ酸配列を有するペプチドである。該ペプチドは、アレルギーを抑制する機能（アレルギー抑制効果）を有するのでアレルギー抑制剤として有用であり、医薬、食品等に応用される。例えば、本第６の発明に係る前記ペプチドを有効成分として配合してアレルギー抑制剤等の医薬、食品等に応用される。これらのうちの医薬としてのアレルギー抑制剤は、アトピー性皮膚炎、気管支喘息、アレルギー性鼻炎等のアレルギー疾患の治療等に供することができ、アレルギー用薬、ヒスタミン放出抑制剤、抗炎症剤としての応用も本発明のアレルギー抑制剤の範ちゅうに含まれる。
なお、前記脂肪蓄積抑制剤の場合と同様、配列番号１９に示されるアミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであってアレルギー抑制効果を有するペプチドも本発明の第６の発明に係るペプチドの範囲に含まれる。このようなペプチドのアミノ酸配列は、配列番号１９で示すアミノ酸配列と７０％以上、さらに好ましくは９０％以上の相同性を有していることが好ましい。
前記第６の発明に係る医薬としてのアレルギー抑制剤は、静脈注射、皮下注射、筋肉内注射、経直腸投与等の非経口の経路で投与するか又は経口投与することが好ましい。また、投与量は、患者の状態や有効成分の分子量等に基づき適宜決定されるが、通常、非経口投与の場合には体重１ｋｇ、１日当たり０．０１ｍｇ〜１ｍｇ程度が好ましく、経口投与の場合には体重１ｋｇ、１日当たり０．１ｍｇ〜１０ｍｇ程度が好ましい。また、前記第６の発明に係るペプチドからなるアレルギー抑制剤は、常法により適宜製剤化することができ、例えば、生理食塩水に３０ｍｇ／ｌ〜３０００ｍｇ／ｌの濃度範囲で溶解したものを用いることができる。また、経口投与の場合には、飲料に添加していわゆるドリンク剤とすることもできる。
本発明の第７の発明に係るペプチドは、配列番号２０、２１又は２２で示されるアミノ酸配列を有するペプチドである。該ペプチドは、血圧を降下させる機能（血圧降下効果）を有するので血圧降下剤として有用であり、医薬、食品等に応用される。例えば、本第７の発明に係る前記ペプチドを有効成分として配合して血圧降下剤等の医薬、食品等に応用される。これらのうちの医薬としての血圧降下剤は、高血圧症の治療及び予防等に用いることができる。
なお、前記脂肪蓄積抑制剤の場合と同様、配列番号２０、２１又は２２に示されるアミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって血圧降下効果を有するペプチドも本発明の第７の発明に係るペプチドの範囲に含まれる。このようなペプチドのアミノ酸配列は、配列番号２０、２１又は２２で示すアミノ酸配列と７０％以上、さらに好ましくは９０％以上の相同性を有していることが好ましい。
前記第７の発明に係る医薬としての血圧降下剤は、静脈注射、皮下注射、筋肉内注射、経直腸投与等の非経口の経路で投与するか又は経口投与することが好ましい。また、投与量は、患者の状態や有効成分の分子量等に基づき適宜決定されるが、通常、非経口投与の場合には体重１ｋｇ、１日当たり０．０１ｍｇ〜１ｍｇ程度が好ましく、経口投与の場合には体重１ｋｇ、１日当たり０．１ｍｇ〜１０ｍｇ程度が好ましい。また、前記第７の発明に係るペプチドからなる血圧降下剤は、常法により適宜製剤化することができ、例えば、生理食塩水に３０ｍｇ／ｌ〜３０００ｍｇ／ｌの濃度範囲で溶解したものを用いることができる。また、経口投与の場合には、飲料に添加していわゆるドリンク剤とすることもできる。
本発明の第８の発明に係るペプチドは、配列番号２３又は２４で示されるアミノ酸配列を有するペプチドである。該ペプチドは、痛みを鎮める機能（鎮痛効果）を有するので鎮痛剤として有用であり、医薬、食品等に応用される。例えば、本第８の発明に係る前記ペプチドを有効成分として配合して鎮痛剤等の医薬、食品等に応用される。これらのうちの医薬としての鎮痛剤は、頭痛・生理痛等の治療等に用いることができる。
なお、前記脂肪蓄積抑制剤の場合と同様、配列番号２３又は２４に示されるアミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって鎮痛効果を有するペプチドも本発明の第８の発明に係るペプチドの範囲に含まれる。このようなペプチドのアミノ酸配列は、配列番号２３又は２４で示すアミノ酸配列と７０％以上、さらに好ましくは９０％以上の相同性を有していることが好ましい。
前記第８の発明に係る医薬としての鎮痛剤は、静脈注射、皮下注射、筋肉内注射、経直腸投与等の非経口の経路で投与するか又は経口投与することが好ましい。また、投与量は、患者の状態や有効成分の分子量等に基づき適宜決定されるが、通常、非経口投与の場合には体重１ｋｇ、１日当たり０．０１ｍｇ〜１ｍｇ程度が好ましく、経口投与の場合には体重１ｋｇ、１日当たり０．１ｍｇ〜１０ｍｇ程度が好ましい。また、前記第８の発明に係るペプチドからなる鎮痛剤は、常法により適宜製剤化することができ、例えば、生理食塩水に３０ｍｇ／ｌ〜３０００ｍｇ／ｌの濃度範囲で溶解したものを用いることができる。また、経口投与の場合には、飲料に添加していわゆるドリンク剤とすることもできる。
本発明の第９の発明に係るペプチドは、配列番号２５、２６、２７、２８、２９、３０、３１又は３２で示されるアミノ酸配列を有するペプチドである。該ペプチドは、中枢神経系機能を促進する機能（中枢神経系機能促進効果）を有するので中枢神経系機能促進剤として有用であり、医薬、食品等に応用される。例えば、本第９の発明に係る前記ペプチドを有効成分として配合して中枢神経系機能促進剤等の医薬、食品等に応用される。これらのうちの医薬としての中枢神経系機能促進剤は、脳虚血障害による脳神経機能障害の予防又は脳神経機能障害の改善（回復治療）等に用いることができ、脳神経機能障害予防治療薬、脳神経機能障害改善治療薬、中枢神経系用薬としての応用も本発明の中枢神経系機能促進剤の範ちゅうに含まれる。
なお、前記脂肪蓄積抑制剤の場合と同様、配列番号２５、２６、２７、２８、２９、３０、３１又は３２に示されるアミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって中枢神経系機能促進効果を有するペプチドも本発明の第９の発明に係るペプチドの範囲に含まれる。このようなペプチドのアミノ酸配列は、配列番号２５、２６、２７、２８、２９、３０、３１又は３２で示すアミノ酸配列と７０％以上、さらに好ましくは９０％以上の相同性を有していることが好ましい。
前記第９の発明に係る医薬としての中枢神経系機能促進剤は、静脈注射、皮下注射、筋肉内注射、経直腸投与等の非経口の経路で投与するか又は経口投与することが好ましい。また、投与量は、患者の状態や有効成分の分子量等に基づき適宜決定されるが、通常、非経口投与の場合には体重１ｋｇ、１日当たり０．０１ｍｇ〜１ｍｇ程度が好ましく、経口投与の場合には体重１ｋｇ、１日当たり０．１ｍｇ〜１０ｍｇ程度が好ましい。また、前記第９の発明に係るペプチドからなる中枢神経系機能促進剤は、常法により適宜製剤化することができ、例えば、生理食塩水に３０ｍｇ／ｌ〜３０００ｍｇ／ｌの濃度範囲で溶解したものを用いることができる。また、経口投与の場合には、飲料に添加していわゆるドリンク剤とすることもできる。
本発明に係る配列表の配列番号１〜３２で示されるアミノ酸配列を有するペプチドは、市販のペプチド合成機を用いて、周知のペプチド化学合成法で容易に合成することができる。合成法としては、固相法または液相法がある。合成されたペプチドは通常の方法に従い精製される。精製方法としては、例えば、イオン交換クロマトグラフィー、逆相液体クロマトグラフィー、アフィニティークロマトグラフィー等が挙げられる。また、本発明のペプチドは、遺伝子改変技術を用いて、本発明によるペプチドのアミノ酸配列に対応する遺伝子及び発現プロモーターを大腸菌、酵母等に組み込み、製造することもできる。得られたペプチドは質量分析器あるいはプロテインシーケンサー等で分析、確認される。
以下実施例を挙げて本発明を具体的に説明する。
実施例１ インスリン産生促進作用
（１）ペプチドの合成
配列番号１に示されるアミノ酸配列を有するペプチドを、ＣＳ ＢＩＯ ＬＴＤ．（Ｃａｌｉｆｏｒｎｉａ，Ｕ．Ｓ．Ａ．）への委託により、以下の要領で合成、精製及び確認を行った。すなわち、固相法にて合成し、逆相液体クロマトグラフィー（Ｖｙｄａｃ社製Ｃ１８カラム、トリフルオロ酢酸／アセトニトリル溶媒系）を用いて純度を検定、また、質量分析器にて生成物の分子量を確認した。
（２）インスリン産生細胞のインスリン産生促進
インスリンを産生するハムスター膵臓細胞であるＨＩＴ細胞（入手先：大日本製薬）を１０％牛胎児血清を含むＲＰＭＩ１６４０培地（入手先：大日本製薬）にて培養し、５％炭酸ガス加湿３７℃恒温器内にて育成した。トリプシン処理により９６穴培養プレートに１×１０４個／穴（ｗｅｌｌ）蒔種し、コンフルーエントになったところで培地を無血清Ｆ１２培地に交換し、８時間培養した。その後、（１）で合成した本発明の配列番号１に示されるアミノ酸配列を有するペプチドを無血清ＲＰＭＩ１６４０培地に溶解し、ＨＩＴ細胞に用量変化をさせながらｗｅｌｌに加えてさらに１２時間培養を継続した。培養後、前記ペプチドによる細胞のインスリン産生促進効果をインスリンのイムノアッセイにより測定し、非処理群に対する産生促進効果を求めた。なお、インスリンのイムノアッセイ及びインスリン産生促進率の算出は具体的には次のように行った。シバヤギ（株）より市販されているインスリン測定キットの手順に従い、細胞培養液上清を用量変化させながら抗インスリン抗体が固定されたウェルに加え抗インスリン抗体溶液と反応させた。検出は、抗体に標識されたビオチンをストレプトアビジン結合ペルオキシダーゼと反応させ、ペルオキシダーゼによる発色を測定した。インスリン濃度は、インスリンの標準曲線から算出した。インスリン産生促進率は前記ペプチドを加えない対照群を１００％とし用量を変化させて加えた群のインスリン産生促進率を求めると次のようになった。結果を表１に示す。

Figure 2003066672
表１から明らかなように、本発明の配列番号１に示されるアミノ酸配列を有するペプチドは、ハムスター由来インスリン産生細胞に対しインスリン産生促進的に作用することが確認された。したがって、本発明の配列番号１に示されるアミノ酸配列を有するペプチドはインスリンの産生を促進し、インスリン産生促進剤としての機能を有し、糖尿病治療薬（インスリン産生促進剤）として有用であることが分かる。また、インスリン産生促進機能を有する食品に活用できることが分かる。
実施例２ 胃酸分泌抑制作用
（１）ペプチドの合成
実施例１と同様にして、配列番号２に示されるアミノ酸配列を有するペプチドを合成、精製及び確認を行った。
（２）ラットにおける胃酸分泌抑制
胃酸分泌抑制効果は、ラット（ウィスター種）を用い、（１）で合成した本発明の配列番号２に示されるアミノ酸配列を有するペプチドと胃酸分泌を促進するガストリンを生理食塩水に溶解した溶液を皮下注射し、１０分後の胃酸分泌を測定することで評価した。ガストリンは４μｇ／ｋｇになるよう、配列番号２に示されるアミノ酸配列を有するペプチドは１０μｇ／ｋｇとなるよう投与した。胃酸分泌は、ラットを固定器に固定し口よりゾンデを胃に入れ胃液を採取し、そのｐＨを測定することで評価した。結果を下記表２に示す。なお、コントロールは、前記ペプチドを投与しなかった対照群についての結果である。
Figure 2003066672
表２から明らかなように、本発明の配列番号２に示されるアミノ酸配列を有するペプチドは、ラットに対し胃酸分泌抑制的に作用することが確認された。したがって、本発明の配列番号２に示されるアミノ酸配列を有するペプチドは胃酸分泌を抑制し、胃酸分泌抑制剤としての機能を有し、胃潰瘍及び十二指腸潰瘍治療薬（胃酸分泌抑制剤）として有用であることが分かる。また、胃酸分泌抑制機能を有する食品に活用できることが分かる。
実施例３ 成長ホルモン産生促進作用
（１）ペプチドの合成
実施例１と同様にして、配列番号３に示されるアミノ酸配列を有するペプチドを合成、精製及び確認を行った。
（２）成長ホルモン産生細胞の成長ホルモン産生促進
成長ホルモンを産生する脳下垂体細胞であるハムスター由来ＧＨ３細胞（入手先：ＩＦＯ（受託番号５０１０５）を１５％牛胎児血清を含むＦ１２培地（入手先：大日本製薬）にて培養し、５％炭酸ガス加湿３７℃恒温器内にて育成した。トリプシン処理により９６穴培養プレートに１×１０４個／穴（ｗｅｌｌ）蒔種し、コンフルーエントになったところで培地を１５％血清Ｆ１２培地に交換し、１２時間培養した。その後、（１）で合成した本発明の配列番号３に示されるアミノ酸配列を有するペプチドを１５％血清Ｆ１２培地に溶解し、用量変化をさせながらｗｅｌｌに加えてさらに３日間培養を継続した。培養後、前記ペプチドによる細胞の成長ホルモン産生促進効果を成長ホルモンのイムノアッセイにより測定し、非処理群に対する産生促進効果を求めた。なお、成長ホルモンのイムノアッセイは、常法であるサンドイッチＥＬＩＳＡにより行った。すなわち、抗成長ホルモン抗体が固定されたウェルに、細胞培養液上清を用量変化させながら加え、室温で１８０分間反応させ、洗浄後、さらにペルオキシダーゼ標識した抗成長ホルモン抗体を加え、室温で６０分間反応させた。洗浄後、ペルオキシダーゼによる発色反応を吸光度測定により測定した。成長ホルモン濃度は、既知濃度の成長ホルモンを用いて同じサンドイッチＥＬＩＳＡを行って得られた標準曲線に基づき求めた。成長ホルモン産生促進率は、ペプチドを加えない対照群を１００％とし、用量を変化させて加えた群の成長ホルモン産生促進率を求めると次のようになった。結果を表３に示す。
Figure 2003066672
表３中、
（＊１）配列番号３に示されるアミノ酸配列を有するペプチド
表３から明らかなように、本発明の配列番号３に示されるアミノ酸配列を有するペプチドは、成長ホルモン産生細胞に対し成長ホルモン産生促進的に作用することが確認された。したがって、本発明の配列番号３に示されるアミノ酸配列を有するペプチドは成長ホルモン産生を促進し、成長ホルモン産生促進剤としての機能を有し、小人病等の治療薬（成長ホルモン産生促進剤）として有用であることが分かる。また、成長ホルモン産生促進機能を有する食品に活用できることが分かる。
実施例４ 血圧降下作用
（１）ペプチドの合成
実施例１と同様にして、配列番号４、５、６、７、８、９、１０、１１又は１２に示されるアミノ酸配列を有するペプチドを合成、精製及び確認を行った。
（２）ラットにおける血圧降下作用
１０週齢の自然発症高血圧モデルラット（ＳＨＲ、雄）に、（１）で合成した本発明の配列番号４、５、６、７、８、９、１０、１１又は１２に示されるアミノ酸配列を有するペプチドを、１０μｇ／ｋｇとなるように腹腔に投与し、またコントロールとして同様に前記ペプチド溶液の代わりに生理食塩水を投与した。ラット尾動脈血圧・脈拍測定装置（ＫＮ−２１０型、夏目製作所製）を用いて投与前及び１時間後の尾動脈血圧を測定した。結果を表４に示す。
Figure 2003066672
表４中、
（＊１）配列番号４に示されるアミノ酸配列を有するペプチド
（＊２）配列番号５に示されるアミノ酸配列を有するペプチド
（＊３）配列番号６に示されるアミノ酸配列を有するペプチド
（＊４）配列番号７に示されるアミノ酸配列を有するペプチド
（＊５）配列番号８に示されるアミノ酸配列を有するペプチド
（＊６）配列番号９に示されるアミノ酸配列を有するペプチド
（＊７）配列番号１０に示されるアミノ酸配列を有するペプチド
（＊８）配列番号１１に示されるアミノ酸配列を有するペプチド
（＊９）配列番号１２に示されるアミノ酸配列を有するペプチド
表４から明らかなように、本発明の配列番号４、５、６、７、８、９、１０、１１又は１２に示されるアミノ酸配列を有するペプチドは、血圧降下作用を有することが確認された。したがって、本発明の配列番号４、５、６、７、８、９、１０、１１又は１２に示されるアミノ酸配列を有するペプチドは血圧降下剤としての機能を有し、高血圧症の治療薬（血圧降下剤）として有用であることが分かる。また、血圧降下機能を有する食品に活用できることが分かる。
実施例５ 脂肪蓄積抑制作用
（１）ペプチドの合成
実施例１と同様にして、配列番号１３、１４、１５、１６、１７及び１８に示されるアミノ酸配列を有するペプチドを合成、精製及び確認を行った。
（２）脂肪蓄積抑制作用（１）
脂肪蓄積する脂肪細胞を１０％牛胎児血清を含むＲＰＭＩ１６４０培地（入手先：大日本製薬）を用いて、５％炭酸ガス加湿３７℃恒温器にて培養した。９６穴培養プレートに１×１０４個／穴（ｗｅｌｌ）播種し、コンフルーエントになったところで培地を無血清Ｆ１２培地に交換し、８時間培養した。その後、（１）で合成した本発明の配列番号１３及び１４に示されるアミノ酸配列を有するペプチドを無血清ＲＰＭＩ１６４０培地に溶解し、用量変化させながらｗｅｌｌに加えてさらに２４時間培養を継続した。培養後、前記ペプチドによる細胞の脂肪蓄積を脂肪顆粒の有無により判定し、非処理群に対する脂肪蓄積率を求めた。なお、脂肪蓄積率は、顕微鏡観察により、各群における脂肪蓄積した細胞数を計数し、前記ペプチドを加えなかった対照群における脂肪蓄積した細胞数に対する百分率で示した。結果を表５に示す。
Figure 2003066672
表５中、
（＊１）配列番号１３に示されるアミノ酸配列を有するペプチド
（＊２）配列番号１４に示されるアミノ酸配列を有するペプチド
表５から明らかなように、本発明の配列番号１３及び１４に示されるアミノ酸配列を有するペプチドは、細胞の脂肪蓄積を阻害し、脂肪蓄積抑制作用（機能）を有することが確認された。したがって、本発明の配列番号１３及び１４に示されるアミノ酸配列を有するペプチドは、脂肪蓄積抑制剤として有用であり、該ペプチドを有効成分として配合して医薬としての高脂血症用剤、肥満治療剤、肥満予防剤等の脂肪蓄積抑制剤、また脂肪蓄積抑制機能を有する食品等に活用できることが分かる。
（３）脂肪蓄積押制作用（２）
ラット（ウイスター種、雄、６週齢）に高脂肪食を自由摂取させ、毎日前記（１）で合成した本発明の配列番号１５、１６、１７及び１８に示されるアミノ酸配列を有するペプチドを腹腔投与し、４週間後に血液を採取し、血中の中性脂肪（ＴＧ）の値を測定した。前記本発明の各ペプチドは生理食塩水に溶解し、投与量１０μｇ／ｋｇとなるよう腹腔に注射した。コントロール群については、生理食塩水を同様に腹腔に注射した。結果を表６に示す。
Figure 2003066672
表６中、
（＊１）配列番号１５に示されるアミノ酸配列を有するペプチド
（＊２）配列番号１６に示されるアミノ酸配列を有するペプチド
（＊３）配列番号１７に示されるアミノ酸配列を有するペプチド
（＊４）配列番号１８に示されるアミノ酸配列を有するペプチド
表６から明らかなように、本発明の配列番号１５、１６、１７及び１８に示されるアミノ酸配列を有するペプチドは、高脂肪食餌ラットの血中中性脂肪増加抑制作用（機能）を有することが確認された。したがって、本発明の配列番号１５、１６、１７及び１８に示されるアミノ酸配列を有するペプチドは、脂肪の蓄積を抑制し、脂肪蓄積抑制剤として有用であり、該ペプチドを有効成分として配合して医薬としての高脂血症用剤、肥満治療剤、肥満予防剤等の脂肪蓄積抑制剤、また脂肪蓄積抑制機能を有する食品等に活用できることが分かる。
実施例６ アレルギー抑制作用
（１）ペプチドの合成
実施例１と同様にして、配列番号１９に示されるアミノ酸配列を有するペプチドを合成、精製及び確認を行った。
（２）アレルギー抑制作用
ヒスタミン遊離抑制作用を、 同時に放出されるβ−ｈｅｘｏｓａｍｉｎｉｄａｓｅ活性を指標として測定した。５×１０５個のＲＢＬ−２Ｈ３細胞（財団法人ヒューマンサイエンス研究資源バンクより購入）を４８ｗｅｌｌ培養プレートの各ｗｅｌｌに播種し、３％ＦＢＳを含むＲＰＭＩ１６４０培養液とともに３７℃、５％ＣＯ２下で２４時間培養した。その培養液に下記の反応混合液２５０μＬを加え、３７℃で１時間反応させた。その後、各ｗｅｌｌから細胞外液１００μＬを分取、残りの外液を除去した。０．２％Ｔｒｉｔｏｎ Ｘ−１００溶液２５０μＬを用いて各ｗｅｌｌの細胞を溶解して細胞内液とし、１００μＬを分取した。β−ｈｅｘｏｓａｍｉｎｉｄａｓｅ活性の測定は分取したサンプルに、５ｍＭのｐ−ｎｉｔｒｏｐｈｅｎｙｌ−２−ａｃｅｔａｍｉｄｏ−２−ｄｅｏｘｙ−β−Ｄ−ｇｌｕｃｏｐｙｒａｎｏｓｉｄｅ（５０ｍＭクエン酸緩衝溶液）４００μＬを加えて反応させ、０．２Ｍグリシン緩衝液（ｐＨ１０．７）１ｍＬ添加にて反応停止後、生成したｐ−ｎｉｔｒｏｐｈｅｎｏｌを４０５ｎｍの吸光度で測定した。細胞外に放出されるβ−ｈｅｘｏｓａｍｉｎｉｄａｓｅ活性の割合を算出し、さらにサンプルを添加した場合のコントロールに対する放出阻害の程度を計算した。
（反応混合液組成）
（１）で合成した本発明の配列番号１９に示されるアミノ酸配列を有するペプチド（０．１ｍＭ〜１０ｍＭ）、ビオチン化マウス抗ＤＮＰ ＩｇＥ抗体（３μｇ／ｍＬ）、アビジン（１μｇ／ｍＬ）それぞれの濃厚溶液を用意し、ｒｅｌｅａｓｉｎｇ ｍｅｄｉｕｍ（１１６．９ｍＭ ＮａＣｌ、５．４ｍＭ ＫＣｌ、０．８ｍＭ ＭｇＳＯ４、５．６ｍＭ Ｄ−ｇｌｕｃｏｓｅ、２５ｍＭ ＨＥＰＥＳ、２．０ｍＭ ＣａＣｌ２、１ｍｇ／ｍｌ ＢＳＡ、ｐＨ７．７）１ｍｌに対し、それぞれ括弧内の濃度になるよう添加する。サンプルペプチドを添加しないものをコントロールとする。結果を表７に示す。
Figure 2003066672
表７から明らかなように、本発明の配列番号１９に示されるアミノ酸配列を有するペプチドは、ヒスタミン放出阻害の指標となるβ−ｈｅｘｏｓａｍｉｎｉｄａｓｅの放出阻害率が高く、アレルギー抑制作用（機能）を有することが確認された。したがって、本発明の配列番号１９に示されるアミノ酸配列を有するペプチドは、アレルギー抑制剤として有用であり、該ペプチドを有効成分として配合して医薬としてのアレルギー用薬、ヒスタミン放出抑制剤、抗炎症剤等のアレルギー抑制剤、またアレルギー抑制機能を有する食品等に活用できることが分かる。
実施例７ 血圧降下作用
（１）ペプチドの合成
実施例１と同様にして、配列番号２０、２１及び２２に示されるアミノ酸配列を有するペプチドを合成、精製及び確認を行った。
（２）ラットにおける血圧降下作用
１０週齢の自然発症高血圧モデルラット（ＳＨＲ、雄）に、（１）で合成した本発明の配列番号２０、２１及び２２に示されるアミノ酸配列を有するペプチドを、１０μｇ／ｋｇとなるように腹腔に投与し、またコントロールとして同様に前記ペプチド溶液の代わりに生理食塩水を投与した。ラット尾動脈血圧・脈拍測定装置（ＫＮ−２１０型、夏目製作所製）を用いて投与前及び１時間後の尾動脈血圧を測定した。結果を表８に示す。
Figure 2003066672
表８中、
（＊１）配列番号２０に示されるアミノ酸配列を有するペプチド
（＊２）配列番号２１に示されるアミノ酸配列を有するペプチド
（＊３）配列番号２２に示されるアミノ酸配列を有するペプチド
表８から明らかなように、本発明の配列番号２０、２１及び２２に示されるアミノ酸配列を有するペプチドは、血圧降下作用（機能）を有することが確認された。したがって、本発明の配列番号２０、２１及び２２に示されるアミノ酸配列を有するペプチドは、血圧降下剤として有用であり、該ペプチドを有効成分として配合して医薬としての血圧降下剤、また血圧降下機能を有する食品等に活用できることが分かる。
実施例８ 鎮痛作用
（１）ペプチドの合成
実施例１と同様にして、配列番号２３及び２４に示されるアミノ酸配列を有するペプチドを合成、精製及び確認を行った。
（２）鎮痛作用
ラット（ウイスター種）を、１群あたり１０匹用いて以下の実験を行った。（１）で合成した本発明の配列番号２３及び２４に示されるアミノ酸配列を有するペプチドを、生理食塩水に溶解して皮下注射し、１０分後の無痛試験で評価した。前記本発明のペプチドは１０μｇ／ｋｇとなるように投与し、コントロールとして生理食塩水のみを投与した。無痛試験は、ラットを加温したホットプレート（６０℃）にのせ、飛び上がるまでの時間を測定することにより、実施した。結果を表９に示す。
Figure 2003066672
表９中、
（＊１）配列番号２３示されるアミノ酸配列を有するペプチド
（＊２）配列番号２４に示されるアミノ酸配列を有するペプチド
表９から明らかなように、本発明の配列番号２３及び２４に示されるアミノ酸配列を有するペプチドは、痛みを抑制し、鎮痛作用（機能）を有することが確認された。したがって、本発明の配列番号２３及び２４に示されるアミノ酸配列を有するペプチドは、鎮痛剤として有用であり、該ペプチドを有効成分として配合して医薬としての鎮痛剤、また鎮痛機能を有する食品等に活用できることが分かる。
実施例９ 中枢神経系機能促進作用
（１）ペプチドの合成
実施例１と同様にして、配列番号２５、２６、２７、２８、２９、３０、３１及び３２に示されるアミノ酸配列を有するペプチドを合成、精製及び確認を行った。
（２）中枢神経系機能促進作用
４週齢のウイスターラット（雄）を用意する。八方放射状迷路を用い、この迷路の空間認識を完成させるべく１週間毎日訓練する。すなわち、同迷路の八つの端に餌を置き、餌を全て取り終えるまで、間違ってすでに餌を取った場所に二度以上進入せず、効率よく八つの餌を得るように学習させる。その後、３週間、投与群には１０ｍｇ／ｋｇの（１）で合成した本発明の配列番号２５、２６、２７、２８、２９、３０、３１及び３２に示されるアミノ酸配列を有するペプチドを腹腔注射し、対照群には生理食塩水を毎日投与する。投与期間終了後、１０分間頚動脈を押えて脳虚血の状態を作り、翌日八方迷路に入れて空間認識記憶の程度を測定する。各通路端の餌の場所に到達する最初の八回のうち、餌の残っている場所に正しく到達した回数を「正選択数」、また、餌を取り終えるまでに、餌のない通路端に到達した回数を「エラー数」とし、カウントした。コントロールに対する正選択数の増加又はエラー数の減少、あるいはその両方は、脳虚血による障害の軽減もしくはその障害からの早期回復作用のあることを示す。結果を表１０に示す。
Figure 2003066672
表１０中、
（＊１）配列番号２５に示されるアミノ酸配列を有するペプチド
（＊２）配列番号２６に示されるアミノ酸配列を有するペプチド
（＊３）配列番号２７に示されるアミノ酸配列を有するペプチド
（＊４）配列番号２８に示されるアミノ酸配列を有するペプチド
（＊５）配列番号２９に示されるアミノ酸配列を有するペプチド
（＊６）配列番号３０に示されるアミノ酸配列を有するペプチド
（＊７）配列番号３１に示されるアミノ酸配列を有するペプチド
（＊８）配列番号３２に示されるアミノ酸配列を有するペプチド
表１０から明らかなように、本発明の配列番号２５、２６、２７、２８、２９、３０、３１及び３２に示されるアミノ酸配列を有するペプチドは、脳虚血による障害を軽減し、またその障害から早期に回復し、中枢神経系機能を促進する機能のあることが確認された。したがって、本発明の配列番号２５、２６、２７、２８、２９、３０、３１及び３２に示されるアミノ酸配列を有するペプチドは、中枢神経系機能促進剤として有用であり、該ペプチドを有効成分として配合して医薬としての脳神経機能障害予防治療薬、脳神経機能障害改善治療薬、中枢神経系用薬、脳神経機能保護剤（薬）等の中枢神経系機能促進剤、また中枢神経系機能を促進する機能を有する食品等に活用できることが分かる。
産業上の利用可能性
以上、詳述したように本発明によれば、特に医薬、食品として有用なペプチドが得られる。本発明の配列表の配列番号１〜３２で示されるアミノ酸配列を有するペプチドは、特に、インスリン産生促進剤、胃酸分泌抑制剤、成長ホルモン産生促進剤、血圧降下剤、脂肪蓄積抑制剤、アレルギー抑制剤、鎮痛剤、中枢神経系機能促進剤等の機能を有し、本発明の配列表の配列番号１〜３２で示されるアミノ酸配列を有するペプチドを用いれば、新規な医薬、食品等を得ることができる。
【配列表】
Figure 2003066672
Figure 2003066672
Figure 2003066672
Figure 2003066672
Figure 2003066672
Figure 2003066672
Figure 2003066672
Figure 2003066672
Figure 2003066672
Figure 2003066672
Figure 2003066672
Technical field
The present invention relates to peptides. More specifically, the present invention relates to a peptide having an insulin production promoting effect, a gastric acid secretion inhibiting effect, a growth hormone production promoting effect, a blood pressure lowering effect, a fat accumulation inhibiting effect, an allergy inhibiting effect, an analgesic effect, and a central nervous system function promoting effect.
Background art
Conventionally, there has been a demand for the development of pharmaceuticals that have excellent efficacy and have no drawbacks such as side effects. On the other hand, it is a well-known fact that a large number of physiologically active substances exist in the living body and are closely related to the maintenance of the normal life activity of the living body. These biologically active substances and synthetic physiologically active substances themselves have the potential as new medicines and foods, and also provide knowledge for developing new medicines and foods.
An object of the present invention is to provide a peptide particularly useful as a medicine or food.
Disclosure of the invention
As a result of intensive studies to solve the above problems, the present inventor has found that a peptide having a specific amino acid sequence has excellent physiological activity, and is particularly useful as a medicine or food, and has completed the present invention. It came to do.
That is, the present invention relates to a peptide having the amino acid sequence represented by SEQ ID NO: 1 in the sequence listing, or one or more amino acids in the amino acid sequence substituted or deleted, or one or more amino acids in the amino acid sequence. Is a peptide having an amino acid sequence inserted or added, the peptide having an insulin production promoting effect, a peptide comprising the peptide as an active ingredient, an insulin production promoter comprising these peptides, and the peptide as an active ingredient It is a medicine or food such as an insulin production promoter.
The present invention also relates to a peptide having the amino acid sequence represented by SEQ ID NO: 2 in the sequence listing, or one or more amino acids in the amino acid sequence substituted or deleted, or one or more amino acids in the amino acid sequence. Is a peptide having an amino acid sequence inserted or added, which has a gastric acid secretion inhibitory effect, a peptide comprising the peptide as an active ingredient, a gastric acid secretion inhibitor comprising these peptides, and the peptide as an active ingredient It is a medicine or food such as a gastric acid secretion inhibitor.
The present invention also relates to a peptide having the amino acid sequence shown by SEQ ID NO: 3 in the sequence listing, or one or more amino acids in the amino acid sequence substituted or deleted, or one or more amino acids in the amino acid sequence. Is a peptide having an amino acid sequence inserted or added, which has a growth hormone production promoting effect, a peptide comprising the peptide as an active ingredient, a growth hormone production promoter comprising these peptides, and the peptide effective It is a pharmaceutical or food such as a growth hormone production promoter contained as an ingredient.
Furthermore, the present invention provides a peptide having the amino acid sequence represented by SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11 or 12 in the sequence listing, or one or more amino acids in the amino acid sequence are substituted. Or a peptide having an amino acid sequence in which one or more amino acids are inserted or added to the amino acid sequence, and having a blood pressure lowering effect, a peptide comprising the peptide as an active ingredient, An antihypertensive agent comprising a peptide, and a medicine or food such as an antihypertensive agent containing the peptide as an active ingredient.
In the present invention, the peptide having the amino acid sequence shown by SEQ ID NO: 13, 14, 15, 16, 17, or 18 in the sequence listing, or one or more amino acids in the amino acid sequence are substituted or deleted, Or a peptide having an amino acid sequence in which one or a plurality of amino acids are inserted or added to the amino acid sequence, the peptide having a fat accumulation-inhibiting effect, a peptide comprising the peptide as an active ingredient, and a fat accumulation composed of these peptides It is a medicine or food such as an inhibitor and a fat accumulation inhibitor containing the peptide as an active ingredient.
The present invention also relates to a peptide having the amino acid sequence represented by SEQ ID NO: 19 in the Sequence Listing, or one or more amino acids in the amino acid sequence substituted or deleted, or one or more amino acids in the amino acid sequence Is a peptide having an amino acid sequence inserted or added, the peptide having an allergic inhibitory effect, a peptide comprising the peptide as an active ingredient, an allergy inhibitor comprising these peptides, and the peptide as an active ingredient It is a medicine or food such as an allergy inhibitor.
The present invention also relates to a peptide having the amino acid sequence represented by SEQ ID NO: 20, 21 or 22, or one or more amino acids in the amino acid sequence substituted or deleted, or one or more amino acids in the amino acid sequence. A peptide having an amino acid sequence into which an amino acid is inserted or added, which has a blood pressure-lowering effect, a peptide containing the peptide as an active ingredient, a blood pressure-lowering agent comprising these peptides, and the peptide as an active ingredient It is a medicine or food such as an antihypertensive agent.
The present invention also relates to a peptide having the amino acid sequence represented by SEQ ID NO: 23 or 24, or one or more amino acids in the amino acid sequence substituted or deleted, or one or more amino acids in the amino acid sequence. A peptide having an inserted or added amino acid sequence, which has an analgesic effect, a peptide containing the peptide as an active ingredient, an analgesic comprising the peptide, and an analgesic containing the peptide as an active ingredient Such a medicine or food.
Furthermore, the present invention relates to a peptide having the amino acid sequence represented by SEQ ID NO: 25, 26, 27, 28, 29, 30, 31, or 32, or one or more amino acids in the amino acid sequence substituted or deleted. Or a peptide having an amino acid sequence in which one or more amino acids are inserted or added to the amino acid sequence, the peptide having a CNS function promoting effect, a peptide comprising the peptide as an active ingredient, and from these peptides A central nervous system function promoter, and a central nervous system function promoter containing the peptide as an active ingredient.
BEST MODE FOR CARRYING OUT THE INVENTION
The peptide which concerns on 1st invention of this invention is a peptide which has an amino acid sequence shown by sequence number 1 of a sequence table. Since the peptide has a function of promoting the production of insulin, it is useful as an insulin production promoter and is applied to medicines, foods and the like. For example, the peptide according to the first invention is blended as an active ingredient and applied to medicines such as insulin production promoters, foods, and the like. Of these, the insulin production promoter as a pharmaceutical can be used for the treatment and prevention of diabetes, and its application as a therapeutic agent for diabetes is also included in the category of the insulin production promoter of the present invention.
In general, a peptide having physiological activity has a substitution or deletion of a small number of amino acid sequences, or a small number of amino acid sequences inserted or added to the amino acid sequence. It is well known to those skilled in the art that the physiological activity may be maintained. Accordingly, a peptide having an amino acid sequence in which one or more amino acids in the amino acid sequence shown in SEQ ID NO: 1 are substituted or deleted, or in which one or more amino acids are inserted or added to the amino acid sequence, Peptides having an insulin production promoting effect are also included in the scope of the peptides according to the first invention of the present invention. The amino acid sequence of such a peptide preferably has a homology of 70% or more, more preferably 90% or more with the amino acid sequence represented by SEQ ID NO: 1.
The insulin production promoter as a medicament according to the first invention is preferably administered by a parenteral route such as intravenous injection, subcutaneous injection, intramuscular injection, rectal administration, or oral administration. The dosage is appropriately determined based on the patient's condition, the molecular weight of the active ingredient, etc. In general, in the case of parenteral administration, the body weight is preferably 1 kg, preferably about 0.01 mg to 1 mg per day. Is preferably about 1 mg to 10 mg per day. Moreover, the insulin production promoter comprising the peptide according to the first invention can be appropriately formulated by a conventional method, for example, one dissolved in physiological saline in a concentration range of 30 mg / l to 3000 mg / l is used. be able to. In addition, in the case of oral administration, it can be added to beverages to form so-called drinks.
The peptide which concerns on 2nd invention of this invention is a peptide which has an amino acid sequence shown by sequence number 2 of a sequence table. Since the peptide has a function of suppressing secretion of gastric acid, it is useful as a gastric acid secretion inhibitor, and is applied to medicines, foods and the like. For example, the peptide according to the second invention is blended as an active ingredient and applied to medicines such as gastric acid secretion inhibitors, foods and the like. Among these, the gastric acid secretion inhibitor as a medicine can be used for the treatment and prevention of gastric ulcer and duodenal ulcer, and its application as a gastrointestinal drug is also included in the category of the gastric acid secretion inhibitor of the present invention.
As in the case of the insulin production promoter, one or more amino acids in the amino acid sequence shown in SEQ ID NO: 2 are substituted or deleted, or one or more amino acids are inserted or added to the amino acid sequence. A peptide having an amino acid sequence and having a gastric acid secretion inhibitory effect is also included in the scope of the peptide according to the second invention of the present invention. The amino acid sequence of such a peptide preferably has a homology of 70% or more, more preferably 90% or more with the amino acid sequence represented by SEQ ID NO: 2.
The gastric acid secretion inhibitor as a medicament according to the second invention is preferably administered by a parenteral route such as intravenous injection, subcutaneous injection, intramuscular injection, rectal administration, or oral administration. The dosage is appropriately determined based on the patient's condition, the molecular weight of the active ingredient, etc. In general, in the case of parenteral administration, the body weight is preferably 1 kg, preferably about 0.01 mg to 1 mg per day. Is preferably about 1 mg to 10 mg per day. In addition, the gastric acid secretion inhibitor comprising the peptide according to the second invention can be appropriately formulated by a conventional method, for example, one dissolved in a physiological saline in a concentration range of 30 mg / l to 3000 mg / l is used. be able to. In addition, in the case of oral administration, it can be added to beverages to form so-called drinks.
The peptide according to the third aspect of the present invention is a peptide having the amino acid sequence represented by SEQ ID NO: 3 in the sequence listing. Since the peptide has a function of promoting the production of growth hormone, it is useful as a growth hormone production promoter and is applied to pharmaceuticals, foods and the like. For example, the peptide according to the third invention is blended as an active ingredient and applied to pharmaceuticals such as growth hormone production promoters, foods and the like. Of these, growth hormone production promoters as pharmaceuticals can be used for the treatment of dwarfism.
As in the case of the insulin production promoter, one or more amino acids in the amino acid sequence shown in SEQ ID NO: 3 are substituted or deleted, or one or more amino acids are inserted or added to the amino acid sequence. A peptide having an amino acid sequence and having a growth hormone production promoting effect is also included in the scope of the peptide according to the third invention of the present invention. The amino acid sequence of such a peptide preferably has a homology of 70% or more, more preferably 90% or more with the amino acid sequence shown in SEQ ID NO: 3.
The growth hormone production promoter as a medicament according to the third invention is preferably administered by a parenteral route such as intravenous injection, subcutaneous injection, intramuscular injection, rectal administration, or oral administration. The dosage is appropriately determined based on the patient's condition, the molecular weight of the active ingredient, etc. In general, in the case of parenteral administration, the body weight is preferably 1 kg, preferably about 0.01 mg to 1 mg per day. Is preferably about 1 mg to 10 mg per day. Moreover, the growth hormone production promoter comprising the peptide according to the third invention can be appropriately formulated by a conventional method, for example, one dissolved in physiological saline in a concentration range of 30 mg / l to 3000 mg / l. Can be used. In addition, in the case of oral administration, it can be added to beverages to form so-called drinks.
The peptide which concerns on 4th invention of this invention is a peptide which has an amino acid sequence shown by sequence number 4, 5, 6, 7, 8, 9, 10, 11 or 12 of a sequence table. Since the peptide has a function of lowering blood pressure, it is useful as a blood pressure lowering agent and is applied to medicines, foods and the like. For example, the peptide according to the fourth invention is blended as an active ingredient and applied to medicines such as blood pressure lowering agents, foods, and the like. Of these, antihypertensive agents as pharmaceuticals can be used for the treatment and prevention of hypertension, and their application as antihypertensive agents is also included in the category of antihypertensive agents of the present invention.
As in the case of the insulin production promoter, one or more amino acids in the amino acid sequence shown in SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11 or 12 are substituted or deleted, Alternatively, a peptide having an amino acid sequence in which one or more amino acids are inserted or added to the amino acid sequence and having a blood pressure lowering effect is also included in the scope of the peptide according to the fourth invention of the present invention. The amino acid sequence of such a peptide has 70% or more, more preferably 90% or more homology with the amino acid sequence shown in SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11 or 12. Preferably it is.
The antihypertensive agent as a medicament according to the fourth invention is preferably administered by a parenteral route such as intravenous injection, subcutaneous injection, intramuscular injection, rectal administration, or oral administration. The dosage is appropriately determined based on the patient's condition, the molecular weight of the active ingredient, etc. In general, in the case of parenteral administration, the body weight is preferably 1 kg, preferably about 0.01 mg to 1 mg per day. Is preferably about 1 mg to 10 mg per day. The antihypertensive agent comprising the peptide according to the fourth invention can be appropriately formulated by a conventional method, and for example, a drug dissolved in physiological saline in a concentration range of 30 mg / l to 3000 mg / l is used. Can do. In addition, in the case of oral administration, it can be added to beverages to form so-called drinks.
The peptide which concerns on 5th invention of this invention is a peptide which has an amino acid sequence shown by sequence number 13, 14, 15, 16, 17, or 18 of a sequence table. Since the peptide has a function of suppressing fat accumulation (fat accumulation inhibiting effect), it is useful as a fat accumulation inhibitor and is applied to medicines, foods and the like. For example, the peptide according to the fifth invention is blended as an active ingredient and applied to medicines such as fat accumulation inhibitors, foods and the like. Of these, the fat accumulation inhibitor as a pharmaceutical can be used for the treatment and prevention of hyperlipidemia, and the application as a hyperlipidemia agent, an obesity treatment agent, and an obesity prevention agent can also be used. Included in the category of accumulation inhibitors.
In general, a peptide having physiological activity has a substitution or deletion of a small number of amino acid sequences, or a small number of amino acid sequences inserted or added to the amino acid sequence. It is well known to those skilled in the art that the physiological activity may be maintained. Accordingly, one or more amino acids in the amino acid sequence shown in SEQ ID NO: 13, 14, 15, 16, 17, or 18 are substituted or deleted, or one or more amino acids are inserted or added to the amino acid sequence. A peptide having an amino acid sequence that has a fat accumulation suppressing effect is also included in the scope of the peptide according to the fifth aspect of the present invention. The amino acid sequence of such a peptide preferably has a homology of 70% or more, more preferably 90% or more with the amino acid sequence represented by SEQ ID NO: 13, 14, 15, 16, 17 or 18.
The fat accumulation inhibitor as a medicament according to the fifth invention is preferably administered by a parenteral route such as intravenous injection, subcutaneous injection, intramuscular injection, rectal administration, or oral administration. The dosage is appropriately determined based on the patient's condition, the molecular weight of the active ingredient, etc. In general, in the case of parenteral administration, the body weight is preferably 1 kg, preferably about 0.01 mg to 1 mg per day. Is preferably about 1 mg to 10 mg per day. In addition, the fat accumulation inhibitor comprising the peptide according to the fifth invention can be appropriately formulated by a conventional method, for example, dissolved in physiological saline in a concentration range of 30 mg / l to 3000 mg / l. Can be used. In addition, in the case of oral administration, it can be added to beverages to form so-called drinks.
The peptide according to the sixth aspect of the present invention is a peptide having the amino acid sequence represented by SEQ ID NO: 19 in the sequence listing. Since the peptide has a function of suppressing allergy (allergy suppressing effect), it is useful as an allergy suppressing agent and applied to medicines, foods and the like. For example, the peptide according to the sixth invention is blended as an active ingredient and applied to medicines such as allergy inhibitors, foods, and the like. Of these, allergy inhibitors as pharmaceuticals can be used for the treatment of allergic diseases such as atopic dermatitis, bronchial asthma, allergic rhinitis, etc., as allergic agents, histamine release inhibitors, anti-inflammatory agents Applications are also included in the category of the allergy suppressing agent of the present invention.
As in the case of the fat accumulation inhibitor, one or more amino acids in the amino acid sequence shown in SEQ ID NO: 19 are substituted or deleted, or one or more amino acids are inserted or added to the amino acid sequence. A peptide having an amino acid sequence that has an allergic inhibitory effect is also included in the scope of the peptide according to the sixth aspect of the present invention. The amino acid sequence of such a peptide preferably has a homology of 70% or more, more preferably 90% or more with the amino acid sequence shown in SEQ ID NO: 19.
The allergy suppressing agent as a medicament according to the sixth invention is preferably administered by a parenteral route such as intravenous injection, subcutaneous injection, intramuscular injection, rectal administration, or oral administration. The dosage is appropriately determined based on the patient's condition, the molecular weight of the active ingredient, etc. In general, in the case of parenteral administration, the body weight is preferably 1 kg, preferably about 0.01 mg to 1 mg per day. Is preferably about 1 mg to 10 mg per day. In addition, the allergy-suppressing agent comprising the peptide according to the sixth invention can be appropriately formulated by a conventional method, for example, one dissolved in physiological saline in a concentration range of 30 mg / l to 3000 mg / l is used. be able to. In addition, in the case of oral administration, it can be added to beverages to form so-called drinks.
The peptide according to the seventh aspect of the present invention is a peptide having the amino acid sequence represented by SEQ ID NO: 20, 21, or 22. Since the peptide has a function of lowering blood pressure (blood pressure lowering effect), it is useful as a blood pressure lowering agent and is applied to medicines, foods and the like. For example, the peptide according to the seventh invention is blended as an active ingredient and applied to medicines such as blood pressure lowering agents, foods, and the like. Of these, antihypertensive agents as pharmaceuticals can be used for the treatment and prevention of hypertension.
As in the case of the fat accumulation inhibitor, one or more amino acids in the amino acid sequence shown in SEQ ID NO: 20, 21, or 22 are substituted or deleted, or one or more amino acids are present in the amino acid sequence. A peptide having an inserted or added amino acid sequence and having a blood pressure lowering effect is also included in the scope of the peptide according to the seventh aspect of the present invention. The amino acid sequence of such a peptide preferably has a homology of 70% or more, more preferably 90% or more, with the amino acid sequence represented by SEQ ID NO: 20, 21 or 22.
The antihypertensive agent as a medicament according to the seventh invention is preferably administered by a parenteral route such as intravenous injection, subcutaneous injection, intramuscular injection, rectal administration, or oral administration. The dosage is appropriately determined based on the patient's condition, the molecular weight of the active ingredient, etc. In general, in the case of parenteral administration, the body weight is preferably 1 kg, preferably about 0.01 mg to 1 mg per day. Is preferably about 1 mg to 10 mg per day. Moreover, the antihypertensive agent comprising the peptide according to the seventh invention can be appropriately formulated by a conventional method, for example, one dissolved in physiological saline in a concentration range of 30 mg / l to 3000 mg / l is used. be able to. In addition, in the case of oral administration, it can be added to beverages to form so-called drinks.
The peptide according to the eighth aspect of the present invention is a peptide having the amino acid sequence represented by SEQ ID NO: 23 or 24. The peptide is useful as an analgesic agent because it has a function to relieve pain (analgesic effect), and is applied to medicines, foods and the like. For example, the peptide according to the eighth invention is blended as an active ingredient and applied to drugs such as analgesics, foods and the like. Of these, analgesics as pharmaceuticals can be used for the treatment of headache, menstrual pain and the like.
As in the case of the fat accumulation inhibitor, one or more amino acids in the amino acid sequence shown in SEQ ID NO: 23 or 24 are substituted or deleted, or one or more amino acids are inserted into the amino acid sequence. Alternatively, a peptide having an added amino acid sequence and having an analgesic effect is also included in the scope of the peptide according to the eighth aspect of the present invention. The amino acid sequence of such a peptide preferably has 70% or more, more preferably 90% or more homology with the amino acid sequence shown in SEQ ID NO: 23 or 24.
The analgesic agent as a medicament according to the eighth invention is preferably administered by a parenteral route such as intravenous injection, subcutaneous injection, intramuscular injection, rectal administration, or oral administration. The dosage is appropriately determined based on the patient's condition, the molecular weight of the active ingredient, etc. In general, in the case of parenteral administration, the body weight is preferably 1 kg, preferably about 0.01 mg to 1 mg per day. Is preferably about 1 mg to 10 mg per day. In addition, the analgesic comprising the peptide according to the eighth invention can be appropriately formulated by a conventional method, for example, using one dissolved in a physiological saline in a concentration range of 30 mg / l to 3000 mg / l. Can do. In addition, in the case of oral administration, it can be added to beverages to form so-called drinks.
The peptide according to the ninth aspect of the present invention is a peptide having the amino acid sequence represented by SEQ ID NO: 25, 26, 27, 28, 29, 30, 31, or 32. Since the peptide has a function of promoting central nervous system function (central nervous system function promoting effect), it is useful as a central nervous system function promoting agent, and is applied to medicines, foods and the like. For example, the peptide according to the ninth aspect of the present invention is blended as an active ingredient and applied to pharmaceuticals such as central nervous system function promoters, foods, and the like. Among these, the central nervous system function promoter as a medicine can be used for prevention of cranial nerve dysfunction due to cerebral ischemic injury or improvement (recovery treatment) of cranial nerve dysfunction. Application as a dysfunction-improving therapeutic agent or a central nervous system drug is also included in the category of the central nervous system function promoter of the present invention.
As in the case of the fat accumulation inhibitor, one or more amino acids in the amino acid sequence represented by SEQ ID NO: 25, 26, 27, 28, 29, 30, 31, or 32 are substituted or deleted, or Peptides having an amino acid sequence in which one or more amino acids are inserted or added to the amino acid sequence and having a CNS function promoting effect are also included in the scope of the peptide according to the ninth aspect of the present invention. The amino acid sequence of such a peptide has 70% or more, more preferably 90% or more homology with the amino acid sequence shown in SEQ ID NO: 25, 26, 27, 28, 29, 30, 31 or 32. Is preferred.
The central nervous system function promoter as a medicament according to the ninth invention is preferably administered by a parenteral route such as intravenous injection, subcutaneous injection, intramuscular injection, or rectal administration, or orally. The dosage is appropriately determined based on the patient's condition, the molecular weight of the active ingredient, etc. In general, in the case of parenteral administration, the body weight is preferably 1 kg, preferably about 0.01 mg to 1 mg per day. Is preferably about 1 mg to 10 mg per day. Moreover, the central nervous system function promoter comprising the peptide according to the ninth invention can be appropriately formulated by a conventional method, for example, dissolved in a physiological saline in a concentration range of 30 mg / l to 3000 mg / l. Things can be used. In addition, in the case of oral administration, it can be added to beverages to form so-called drinks.
The peptide having the amino acid sequence shown by SEQ ID NO: 1 to 32 in the sequence listing according to the present invention can be easily synthesized by a known peptide chemical synthesis method using a commercially available peptide synthesizer. Examples of the synthesis method include a solid phase method and a liquid phase method. The synthesized peptide is purified according to a usual method. Examples of the purification method include ion exchange chromatography, reverse phase liquid chromatography, affinity chromatography and the like. The peptide of the present invention can also be produced by incorporating a gene corresponding to the amino acid sequence of the peptide of the present invention and an expression promoter into Escherichia coli, yeast or the like using gene modification technology. The obtained peptide is analyzed and confirmed by a mass spectrometer or a protein sequencer.
Hereinafter, the present invention will be specifically described with reference to examples.
Example 1 Insulin production promoting action
(1) Peptide synthesis
A peptide having the amino acid sequence shown in SEQ ID NO: 1 was prepared using CS BIO LTD. The synthesis, purification and confirmation were carried out in the following manner on consignment to (California, USA). In other words, it was synthesized by a solid phase method, purity was tested using reverse phase liquid chromatography (C18 column manufactured by Vydac, trifluoroacetic acid / acetonitrile solvent system), and the molecular weight of the product was confirmed using a mass spectrometer. did.
(2) Promotion of insulin production by insulin-producing cells
HIT cells (source: Dainippon Pharmaceutical), which are hamster pancreatic cells that produce insulin, are cultured in RPMI 1640 medium (source: Dainippon Pharmaceutical) containing 10% fetal calf serum, and 5% carbon dioxide humidified at 37 ° C. Raised in the vessel. 1x10 in 96-well culture plate by trypsinization 4 When the cells were seeded per well and became confluent, the medium was replaced with serum-free F12 medium and cultured for 8 hours. Thereafter, the peptide having the amino acid sequence represented by SEQ ID NO: 1 of the present invention synthesized in (1) was dissolved in serum-free RPMI1640 medium, added to the well while changing the dose of HIT cells, and further cultured for 12 hours. . After the culture, the insulin production promoting effect of the cells by the peptide was measured by insulin immunoassay, and the production promoting effect on the untreated group was determined. Specifically, the immunoassay of insulin and the calculation of the insulin production promotion rate were performed as follows. In accordance with the procedure of an insulin measurement kit commercially available from Shiba Goat Co., Ltd., the cell culture supernatant was added to a well in which the anti-insulin antibody was immobilized while changing the dose, and reacted with the anti-insulin antibody solution. For detection, biotin labeled on the antibody was reacted with streptavidin-conjugated peroxidase, and color development by peroxidase was measured. Insulin concentration was calculated from a standard curve of insulin. The insulin production promotion rate was as follows when the control group to which the peptide was not added was 100%, and the insulin production promotion rate of the group added by changing the dose was determined. The results are shown in Table 1.
Figure 2003066672
As is clear from Table 1, it was confirmed that the peptide having the amino acid sequence represented by SEQ ID NO: 1 of the present invention acts to promote insulin production on hamster-derived insulin-producing cells. Therefore, the peptide having the amino acid sequence represented by SEQ ID NO: 1 of the present invention promotes insulin production, has a function as an insulin production promoter, and is useful as a therapeutic agent for diabetes (insulin production promoter). I understand. Moreover, it turns out that it can utilize for the foodstuff which has an insulin production promotion function.
Example 2 Inhibition of gastric acid secretion
(1) Peptide synthesis
In the same manner as in Example 1, a peptide having the amino acid sequence represented by SEQ ID NO: 2 was synthesized, purified, and confirmed.
(2) Suppression of gastric acid secretion in rats
The gastric acid secretion inhibitory effect is obtained by using a rat (Wistar species), a solution in which a peptide having the amino acid sequence shown in SEQ ID NO: 2 of the present invention synthesized in (1) and gastrin that promotes gastric acid secretion are dissolved in physiological saline. Subcutaneous injection was performed, and evaluation was made by measuring gastric acid secretion 10 minutes later. Gastrin was administered at 4 μg / kg, and the peptide having the amino acid sequence shown in SEQ ID NO: 2 was administered at 10 μg / kg. Gastric acid secretion was evaluated by fixing a rat to a fixator, putting a sonde into the stomach from the mouth, collecting gastric juice, and measuring its pH. The results are shown in Table 2 below. In addition, control is the result about the control group which did not administer the said peptide.
Figure 2003066672
As is clear from Table 2, it was confirmed that the peptide having the amino acid sequence represented by SEQ ID NO: 2 of the present invention acts on the rat in a manner of inhibiting gastric acid secretion. Therefore, the peptide having the amino acid sequence represented by SEQ ID NO: 2 of the present invention suppresses gastric acid secretion, has a function as a gastric acid secretion inhibitor, and is useful as a therapeutic agent for gastric ulcer and duodenal ulcer (gastric acid secretion inhibitor). I understand that. Moreover, it turns out that it can utilize for the foodstuff which has a gastric acid secretion suppression function.
Example 3 Growth hormone production promoting action
(1) Peptide synthesis
In the same manner as in Example 1, a peptide having the amino acid sequence represented by SEQ ID NO: 3 was synthesized, purified, and confirmed.
(2) Promotion of growth hormone production by growth hormone-producing cells
A hamster-derived GH3 cell that is a pituitary cell that produces growth hormone (source: IFO (Accession No. 50105) is cultured in F12 medium (source: Dainippon Pharmaceutical) containing 15% fetal bovine serum, and 5% Growing in a carbon dioxide humidified incubator at 37 ° C. Trypsin treatment in a 96-well culture plate 1 × 10 4 When the cells were seeded per well and became confluent, the medium was replaced with 15% serum F12 medium and cultured for 12 hours. Thereafter, the peptide having the amino acid sequence represented by SEQ ID NO: 3 of the present invention synthesized in (1) was dissolved in 15% serum F12 medium, added to the well while changing the dose, and further cultured for 3 days. After culturing, the growth hormone production-promoting effect of cells by the peptide was measured by growth hormone immunoassay to determine the production-promoting effect for the untreated group. The growth hormone immunoassay was performed by a conventional sandwich ELISA. That is, the cell culture supernatant is added to the wells to which the anti-growth hormone antibody has been fixed while changing the dose, reacted at room temperature for 180 minutes, washed, and then added with peroxidase-labeled anti-growth hormone antibody, and at room temperature for 60 minutes. Reacted. After washing, the color reaction by peroxidase was measured by absorbance measurement. The growth hormone concentration was determined based on a standard curve obtained by performing the same sandwich ELISA using a known concentration of growth hormone. The growth hormone production promotion rate was as follows when the control group to which no peptide was added was 100%, and the growth hormone production promotion rate of the group added by changing the dose was determined. The results are shown in Table 3.
Figure 2003066672
In Table 3,
(* 1) Peptide having the amino acid sequence shown in SEQ ID NO: 3
As is clear from Table 3, it was confirmed that the peptide having the amino acid sequence represented by SEQ ID NO: 3 of the present invention acts on growth hormone-producing cells to promote growth hormone production. Therefore, the peptide having the amino acid sequence represented by SEQ ID NO: 3 of the present invention promotes growth hormone production, has a function as a growth hormone production promoter, and is a therapeutic agent for dwarf diseases (growth hormone production promoter). It turns out that it is useful. Moreover, it turns out that it can utilize for the food which has a growth hormone production promotion function.
Example 4 Blood pressure lowering effect
(1) Peptide synthesis
In the same manner as in Example 1, a peptide having the amino acid sequence shown in SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11 or 12 was synthesized, purified, and confirmed.
(2) Blood pressure lowering effect in rats
A 10-week-old spontaneously hypertensive model rat (SHR, male) was subjected to the amino acid sequence represented by SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11 or 12 of the present invention synthesized in (1). The peptide having the peptide was administered to the abdominal cavity at 10 μg / kg, and as a control, physiological saline was administered instead of the peptide solution. Using a rat tail artery blood pressure / pulse measuring device (KN-210, manufactured by Natsume Seisakusho), the tail artery blood pressure was measured before administration and after 1 hour. The results are shown in Table 4.
Figure 2003066672
In Table 4,
(* 1) Peptide having the amino acid sequence shown in SEQ ID NO: 4
(* 2) Peptide having the amino acid sequence shown in SEQ ID NO: 5
(* 3) Peptide having the amino acid sequence shown in SEQ ID NO: 6
(* 4) Peptide having the amino acid sequence shown in SEQ ID NO: 7
(* 5) Peptide having the amino acid sequence shown in SEQ ID NO: 8
(* 6) Peptide having the amino acid sequence shown in SEQ ID NO: 9
(* 7) Peptide having the amino acid sequence shown in SEQ ID NO: 10
(* 8) Peptide having the amino acid sequence shown in SEQ ID NO: 11
(* 9) Peptide having the amino acid sequence shown in SEQ ID NO: 12
As is clear from Table 4, it was confirmed that the peptide having the amino acid sequence shown in SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11 or 12 of the present invention has a blood pressure lowering effect. . Therefore, the peptide having the amino acid sequence represented by SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11 or 12 of the present invention has a function as a blood pressure lowering agent, and is a therapeutic agent for hypertension (blood pressure It turns out that it is useful as a depressant. Moreover, it turns out that it can utilize for the foodstuff which has a blood pressure lowering function.
Example 5 Inhibition of fat accumulation
(1) Peptide synthesis
In the same manner as in Example 1, peptides having the amino acid sequences shown in SEQ ID NOs: 13, 14, 15, 16, 17, and 18 were synthesized, purified, and confirmed.
(2) Fat accumulation inhibitory action (1)
The fat cells that accumulate fat were cultured in a 10% fetal bovine serum RPMI1640 medium (source: Dainippon Pharmaceutical) in a 5% carbon dioxide humidified 37 ° C incubator. 1 × 10 in 96-well culture plate 4 When the cells were inoculated, the medium was replaced with serum-free F12 medium and cultured for 8 hours. Thereafter, the peptides having the amino acid sequences shown in SEQ ID NOS: 13 and 14 of the present invention synthesized in (1) were dissolved in serum-free RPMI 1640 medium, added to wells while changing the dose, and further cultured for 24 hours. After culturing, cell fat accumulation by the peptide was determined by the presence or absence of fat granules, and the fat accumulation rate for the untreated group was determined. The fat accumulation rate was counted by counting the number of fat accumulated cells in each group by microscopic observation and expressed as a percentage of the number of fat accumulated cells in the control group to which the peptide was not added. The results are shown in Table 5.
Figure 2003066672
In Table 5,
(* 1) Peptide having the amino acid sequence shown in SEQ ID NO: 13
(* 2) Peptide having the amino acid sequence shown in SEQ ID NO: 14
As is clear from Table 5, it was confirmed that the peptides having the amino acid sequences shown in SEQ ID NOs: 13 and 14 of the present invention inhibit fat accumulation in cells and have a fat accumulation suppressing action (function). Therefore, the peptides having the amino acid sequences shown in SEQ ID NOs: 13 and 14 of the present invention are useful as fat accumulation inhibitors, and are formulated as active ingredients for hyperlipidemia and treatment for obesity. It can be seen that the present invention can be used for fat accumulation inhibitors such as agents and anti-obesity agents, and foods having a function of inhibiting fat accumulation.
(3) For fat accumulation press production (2)
Rats (Wistar species, male, 6 weeks old) were allowed to freely ingest a high fat diet, and the peptide having the amino acid sequence shown in SEQ ID NOs: 15, 16, 17 and 18 of the present invention synthesized in the above (1) was intraperitoneally injected. The blood was collected 4 weeks after administration, and the value of triglyceride (TG) in the blood was measured. Each peptide of the present invention was dissolved in physiological saline and injected into the abdominal cavity so that the dose was 10 μg / kg. For the control group, physiological saline was similarly injected into the peritoneal cavity. The results are shown in Table 6.
Figure 2003066672
In Table 6,
(* 1) Peptide having the amino acid sequence shown in SEQ ID NO: 15
(* 2) Peptide having the amino acid sequence shown in SEQ ID NO: 16
(* 3) Peptide having the amino acid sequence shown in SEQ ID NO: 17
(* 4) Peptide having the amino acid sequence shown in SEQ ID NO: 18
As is clear from Table 6, the peptide having the amino acid sequence shown in SEQ ID NOs: 15, 16, 17 and 18 of the present invention has an inhibitory action (function) on blood neutral fat increase in high-fat diet rats. confirmed. Therefore, the peptide having the amino acid sequence shown in SEQ ID NOs: 15, 16, 17 and 18 of the present invention suppresses fat accumulation and is useful as a fat accumulation inhibitor, and is formulated with the peptide as an active ingredient. It can be seen that it can be used for fat accumulation inhibitors such as hyperlipidemia agents, obesity treatment agents, obesity prevention agents, and the like, and foods having a function of inhibiting fat accumulation.
Example 6 Antiallergic action
(1) Peptide synthesis
In the same manner as in Example 1, a peptide having the amino acid sequence represented by SEQ ID NO: 19 was synthesized, purified, and confirmed.
(2) Allergy suppression effect
The inhibitory effect on histamine release was measured using the simultaneously released β-hexosaminidase activity as an index. 5 × 10 5 RBL-2H3 cells (purchased from Human Science Research Resource Bank) were seeded in each well of a 48-well culture plate, and 37 ° C., 5% CO together with RPMI1640 culture solution containing 3% FBS. 2 The cells were cultured for 24 hours. 250 μL of the following reaction mixture was added to the culture and reacted at 37 ° C. for 1 hour. Thereafter, 100 μL of extracellular fluid was collected from each well, and the remaining external fluid was removed. Each well cell was lysed using 250 μL of 0.2% Triton X-100 solution to prepare an intracellular solution, and 100 μL was collected. β-hexosaminidase activity was measured by adding 400 μL of 5 mM p-nitrophenyl-2-acetamido-2-deoxy-β-D-glucopyranoside (50 mM citrate buffer solution) to the collected sample, and 0.2 M glycine After stopping the reaction by adding 1 mL of a buffer solution (pH 10.7), the produced p-nitrophenol was measured at an absorbance of 405 nm. The ratio of β-hexosaminidase activity released out of the cells was calculated, and the degree of release inhibition relative to the control when a sample was further added was calculated.
(Reaction mixture composition)
Concentrations of peptides (0.1 mM to 10 mM) having the amino acid sequence shown in SEQ ID NO: 19 of the present invention synthesized in (1), biotinylated mouse anti-DNP IgE antibody (3 μg / mL), and avidin (1 μg / mL) A solution was prepared and releasing medium (116.9 mM NaCl, 5.4 mM KCl, 0.8 mM MgSO 4 5.6 mM D-glucose, 25 mM HEPES, 2.0 mM CaCl 2 1 mg / ml BSA, pH 7.7) Add to 1 ml each so that the concentration is in parentheses. A sample without added sample peptide is used as a control. The results are shown in Table 7.
Figure 2003066672
As is apparent from Table 7, the peptide having the amino acid sequence represented by SEQ ID NO: 19 of the present invention has a high release inhibition rate of β-hexosaminidase, which is an index of inhibition of histamine release, and has an allergy suppressing action (function). Was confirmed. Therefore, the peptide having the amino acid sequence represented by SEQ ID NO: 19 of the present invention is useful as an allergy inhibitor, and contains the peptide as an active ingredient to prepare an allergy drug, histamine release inhibitor, anti-inflammatory agent as a medicine It can be seen that it can be used for allergy-suppressing agents such as foods having allergy-suppressing functions.
Example 7 Blood pressure lowering effect
(1) Peptide synthesis
In the same manner as in Example 1, peptides having the amino acid sequences shown in SEQ ID NOs: 20, 21, and 22 were synthesized, purified, and confirmed.
(2) Blood pressure lowering effect in rats
To a 10-week-old spontaneously hypertensive model rat (SHR, male), the peptide having the amino acid sequence shown in SEQ ID NOs: 20, 21 and 22 of the present invention synthesized in (1) was peritoneally injected so that the concentration was 10 μg / kg. As a control, physiological saline was administered instead of the peptide solution. Using a rat tail artery blood pressure / pulse measuring device (KN-210, manufactured by Natsume Seisakusho), the tail artery blood pressure was measured before administration and after 1 hour. The results are shown in Table 8.
Figure 2003066672
In Table 8,
(* 1) Peptide having the amino acid sequence shown in SEQ ID NO: 20
(* 2) Peptide having the amino acid sequence shown in SEQ ID NO: 21
(* 3) Peptide having the amino acid sequence shown in SEQ ID NO: 22
As is clear from Table 8, it was confirmed that the peptides having the amino acid sequences shown in SEQ ID NOs: 20, 21, and 22 of the present invention have a blood pressure lowering action (function). Therefore, the peptide having the amino acid sequence shown in SEQ ID NOs: 20, 21, and 22 of the present invention is useful as an antihypertensive agent, and an antihypertensive agent as a pharmaceutical comprising the peptide as an active ingredient, or an antihypertensive function It can be seen that it can be used for foods having
Example 8 Analgesic Action
(1) Peptide synthesis
In the same manner as in Example 1, peptides having the amino acid sequences shown in SEQ ID NOs: 23 and 24 were synthesized, purified, and confirmed.
(2) Analgesic action
The following experiment was conducted using 10 rats (Wistar species) per group. Peptides having the amino acid sequences shown in SEQ ID NOs: 23 and 24 of the present invention synthesized in (1) were dissolved in physiological saline and injected subcutaneously, and evaluated in a painless test 10 minutes later. The peptide of the present invention was administered at 10 μg / kg, and physiological saline alone was administered as a control. The painless test was carried out by placing the rat on a heated hot plate (60 ° C.) and measuring the time to jump. The results are shown in Table 9.
Figure 2003066672
In Table 9,
(* 1) Peptide having the amino acid sequence shown in SEQ ID NO: 23
(* 2) Peptide having the amino acid sequence shown in SEQ ID NO: 24
As is clear from Table 9, it was confirmed that the peptides having the amino acid sequences shown in SEQ ID NOs: 23 and 24 of the present invention suppress pain and have analgesic action (function). Therefore, the peptide having the amino acid sequence shown in SEQ ID NOs: 23 and 24 of the present invention is useful as an analgesic, and is formulated into an analgesic as a medicine by combining the peptide as an active ingredient, a food having an analgesic function, etc. You can see that it can be used.
Example 9 Central nervous system function promoting action
(1) Peptide synthesis
In the same manner as in Example 1, peptides having the amino acid sequences shown in SEQ ID NOs: 25, 26, 27, 28, 29, 30, 31, and 32 were synthesized, purified, and confirmed.
(2) Central nervous system function promoting action
A 4-week-old Wistar rat (male) is prepared. Using the Happo radial maze, train daily for a week to complete spatial recognition of this maze. That is, place food on the eight ends of the maze, and let them learn to obtain eight foods efficiently, without entering the place where they have already accidentally taken food more than once until all the food is taken. Thereafter, for 3 weeks, the administration group was injected intraperitoneally with a peptide having the amino acid sequence of SEQ ID NO: 25, 26, 27, 28, 29, 30, 31 and 32 of the present invention synthesized at 10 mg / kg (1). In the control group, physiological saline is administered every day. After completion of the administration period, the carotid artery is pressed for 10 minutes to create a state of cerebral ischemia, and the next day, it is placed in the Happo Maze to measure the degree of spatial recognition memory. Of the first eight times to reach the bait location at each aisle end, the number of times that the remaining bait is correctly reached is the “positive selection number”, and before the bait is taken, The number of times reached was regarded as the “number of errors” and counted. An increase in the number of positive selections relative to the control and / or a decrease in the number of errors indicate that there is a reduction in damage due to cerebral ischemia or an early recovery action from the damage. The results are shown in Table 10.
Figure 2003066672
In Table 10,
(* 1) Peptide having the amino acid sequence shown in SEQ ID NO: 25
(* 2) Peptide having the amino acid sequence shown in SEQ ID NO: 26
(* 3) Peptide having the amino acid sequence shown in SEQ ID NO: 27
(* 4) Peptide having the amino acid sequence shown in SEQ ID NO: 28
(* 5) Peptide having the amino acid sequence shown in SEQ ID NO: 29
(* 6) Peptide having the amino acid sequence shown in SEQ ID NO: 30
(* 7) Peptide having the amino acid sequence shown in SEQ ID NO: 31
(* 8) Peptide having the amino acid sequence shown in SEQ ID NO: 32
As is apparent from Table 10, the peptide having the amino acid sequence shown in SEQ ID NOs: 25, 26, 27, 28, 29, 30, 31, and 32 of the present invention reduces damage caused by cerebral ischemia. It was confirmed that it has a function to recover from the early stage and promote the central nervous system function. Therefore, the peptide having the amino acid sequence shown in SEQ ID NOs: 25, 26, 27, 28, 29, 30, 31, and 32 of the present invention is useful as a central nervous system function promoter, and contains the peptide as an active ingredient. CNS function promoters such as cranial nerve dysfunction preventive and therapeutic drugs, cranial nerve dysfunction remedies, central nervous system drugs, cranial nerve function protecting agents (drugs), and functions that promote central nervous system functions It can be seen that it can be used for foods having
Industrial applicability
As described above in detail, according to the present invention, a peptide particularly useful as a pharmaceutical or food can be obtained. Peptides having the amino acid sequences shown in SEQ ID NOs: 1 to 32 in the sequence listing of the present invention are, in particular, insulin production promoters, gastric acid secretion inhibitors, growth hormone production promoters, blood pressure lowering agents, fat accumulation inhibitors, allergy inhibitors If a peptide having an amino acid sequence represented by SEQ ID NOs: 1 to 32 in the sequence listing of the present invention having functions such as an agent, an analgesic, and a central nervous system function promoter is obtained, a novel medicine, food, etc. can be obtained. Can do.
[Sequence Listing]
Figure 2003066672
Figure 2003066672
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Claims (45)

配列表の配列番号１で示されるアミノ酸配列を有するペプチド、或いは該アミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって、インスリン産生促進効果を有するペプチド。A peptide having the amino acid sequence shown in SEQ ID NO: 1 in the sequence listing, or one or more amino acids in the amino acid sequence are substituted or deleted, or one or more amino acids are inserted or added to the amino acid sequence A peptide having an amino acid sequence and having an effect of promoting insulin production. 配列表の配列番号１で示されるアミノ酸配列を有するペプチドを有効成分とする請求の範囲第１項記載のペプチド。2. The peptide according to claim 1, comprising a peptide having the amino acid sequence represented by SEQ ID NO: 1 in the sequence listing as an active ingredient. 請求の範囲第１又は２項記載のペプチドからなるインスリン産生促進剤。An insulin production promoter comprising the peptide according to claim 1 or 2. 請求の範囲第１又は２項記載のペプチドを有効成分として含有する医薬又は食品。A pharmaceutical or food containing the peptide according to claim 1 or 2 as an active ingredient. インスリン産生促進剤である請求の範囲第４項記載の医薬又は食品。The medicine or food according to claim 4, which is an insulin production promoter. 配列表の配列番号２で示されるアミノ酸配列を有するペプチド、或いは該アミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって、胃酸分泌抑制効果を有するペプチド。A peptide having the amino acid sequence shown in SEQ ID NO: 2 in the sequence listing, or one or more amino acids in the amino acid sequence are substituted or deleted, or one or more amino acids are inserted or added to the amino acid sequence A peptide having an amino acid sequence and having a gastric acid secretion inhibiting effect. 配列表の配列番号２で示されるアミノ酸配列を有するペプチドを有効成分とする請求の範囲第６項記載のペプチド。The peptide according to claim 6, comprising a peptide having the amino acid sequence represented by SEQ ID NO: 2 in the sequence listing as an active ingredient. 請求の範囲第６又は７項記載のペプチドからなる胃酸分泌抑制剤。A gastric acid secretion inhibitor comprising the peptide according to claim 6 or 7. 請求の範囲第６又は７項記載のペプチドを有効成分として含有する医薬又は食品。A medicine or food containing the peptide according to claim 6 or 7 as an active ingredient. 胃酸分泌抑制剤である請求の範囲第９項記載の医薬又は食品。The medicine or food according to claim 9, which is a gastric acid secretion inhibitor. 配列表の配列番号３で示されるアミノ酸配列を有するペプチド、或いは該アミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって、成長ホルモン産生促進効果を有するペプチド。A peptide having the amino acid sequence shown in SEQ ID NO: 3 in the sequence listing, or one or more amino acids in the amino acid sequence are substituted or deleted, or one or more amino acids are inserted or added to the amino acid sequence A peptide having an amino acid sequence and having an effect of promoting growth hormone production. 配列表の配列番号３で示されるアミノ酸配列を有するペプチドを有効成分とする請求の範囲第１１項記載のペプチド。The peptide according to claim 11, comprising a peptide having the amino acid sequence represented by SEQ ID NO: 3 in the sequence listing as an active ingredient. 請求の範囲第１１又は１２項記載のペプチドからなる成長ホルモン産生促進剤。A growth hormone production promoter comprising the peptide according to claim 11 or 12. 請求の範囲第１１又は１２項記載のペプチドを有効成分として含有する医薬又は食品。A medicine or food containing the peptide according to claim 11 or 12 as an active ingredient. 成長ホルモン産生促進剤である請求の範囲第１４項記載の医薬又は食品。The medicine or food according to claim 14, which is a growth hormone production promoter. 配列表の配列番号４、５、６、７、８、９、１０、１１又は１２で示されるアミノ酸配列を有するペプチド、或いは該アミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって、血圧降下効果を有するペプチド。A peptide having the amino acid sequence represented by SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11 or 12 in the sequence listing, or one or more amino acids in the amino acid sequence are substituted or deleted, Alternatively, a peptide having an amino acid sequence in which one or more amino acids are inserted or added to the amino acid sequence, and having a blood pressure lowering effect. 配列表の配列番号４、５、６、７、８、９、１０、１１又は１２で示されるアミノ酸配列を有するペプチドを有効成分とする請求の範囲第１６項記載のペプチド。The peptide according to claim 16, comprising a peptide having an amino acid sequence represented by SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11 or 12 in the sequence listing as an active ingredient. 請求の範囲第１６又は１７項記載のペプチドからなる血圧降下剤。An antihypertensive agent comprising the peptide according to claim 16 or 17. 請求の範囲第１６又は１７項記載のペプチドを有効成分として含有する医薬又は食品。A medicine or food containing the peptide according to claim 16 or 17 as an active ingredient. 血圧降下剤である請求の範囲第１９項記載の医薬又は食品。20. The pharmaceutical or food according to claim 19, which is an antihypertensive agent. 配列表の配列番号１３、１４、１５、１６、１７又は１８で示されるアミノ酸配列を有するペプチド、或いは該アミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって、脂肪蓄積抑制効果を有するペプチド。A peptide having the amino acid sequence represented by SEQ ID NO: 13, 14, 15, 16, 17 or 18 in the sequence listing, or one or more amino acids in the amino acid sequence are substituted or deleted, or 1 in the amino acid sequence Alternatively, a peptide having an amino acid sequence into which a plurality of amino acids are inserted or added, and having a fat accumulation inhibitory effect. 配列表の配列番号１３、１４、１５、１６、１７又は１８で示されるアミノ酸配列を有するペプチドを有効成分とする請求の範囲第２１項記載のペプチド。The peptide according to claim 21, wherein the peptide having the amino acid sequence represented by SEQ ID NO: 13, 14, 15, 16, 17, or 18 in the sequence listing is an active ingredient. 請求の範囲第２１又は２２項記載のペプチドからなる脂肪蓄積抑制剤。A fat accumulation inhibitor comprising the peptide according to claim 21 or 22. 請求の範囲第２１又は２２項記載のペプチドを有効成分として含有する医薬又は食品。A medicine or food containing the peptide according to claim 21 or 22 as an active ingredient. 脂肪蓄積抑制剤である請求の範囲第２４項記載の医薬又は食品。25. The pharmaceutical or food according to claim 24, which is a fat accumulation inhibitor. 配列表の配列番号１９で示されるアミノ酸配列を有するペプチド、或いは該アミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって、アレルギー抑制効果を有するペプチド。A peptide having the amino acid sequence shown in SEQ ID NO: 19 in the sequence listing, or one or more amino acids in the amino acid sequence are substituted or deleted, or one or more amino acids are inserted or added to the amino acid sequence A peptide having an amino acid sequence, which has an allergy suppressing effect. 配列表の配列番号１９で示されるアミノ酸配列を有するペプチドを有効成分とする請求の範囲第２６項記載のペプチド。27. The peptide according to claim 26, comprising a peptide having the amino acid sequence represented by SEQ ID NO: 19 in the sequence listing as an active ingredient. 請求の範囲第２６又は２７項記載のペプチドからなるアレルギー抑制剤。An allergy suppressing agent comprising the peptide according to claim 26 or 27. 請求の範囲第２６又は２７項記載のペプチドを有効成分として含有する医薬又は食品。A pharmaceutical or food containing the peptide according to claim 26 or 27 as an active ingredient. アレルギー抑制剤である請求の範囲第２９項記載の医薬又は食品。30. The pharmaceutical or food according to claim 29, which is an allergy inhibitor. 配列番号２０、２１又は２２で示されるアミノ酸配列を有するペプチド、或いは該アミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって、血圧降下効果を有するペプチド。A peptide having the amino acid sequence represented by SEQ ID NO: 20, 21 or 22, or one or more amino acids in the amino acid sequence are substituted or deleted, or one or more amino acids are inserted or added to the amino acid sequence A peptide having an amino acid sequence that has a blood pressure lowering effect. 配列番号２０、２１又は２２で示されるアミノ酸配列を有するペプチドを有効成分とする請求の範囲第３１項記載のペプチド。32. The peptide according to claim 31, wherein the peptide having the amino acid sequence represented by SEQ ID NO: 20, 21, or 22 is an active ingredient. 請求の範囲第３１又は３２項記載のペプチドからなる血圧降下剤。An antihypertensive agent comprising the peptide according to claim 31 or 32. 請求の範囲第３１又は３２項記載のペプチドを有効成分として含有する医薬又は食品。A medicine or food containing the peptide according to claim 31 or 32 as an active ingredient. 血圧降下剤である請求の範囲第３４項記載の医薬又は食品。The medicine or food according to claim 34, which is a blood pressure lowering agent. 配列表の配列番号２３又は２４で示されるアミノ酸配列を有するペプチド、或いは該アミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって、鎮痛効果を有するペプチド。A peptide having the amino acid sequence represented by SEQ ID NO: 23 or 24 in the sequence listing, or one or more amino acids in the amino acid sequence are substituted or deleted, or one or more amino acids are inserted into the amino acid sequence, or A peptide having an added amino acid sequence and having an analgesic effect. 配列表の配列番号２３又は２４で示されるアミノ酸配列を有するペプチドを有効成分とする請求の範囲第３６項記載のペプチド。The peptide according to claim 36, comprising a peptide having an amino acid sequence represented by SEQ ID NO: 23 or 24 in the sequence listing as an active ingredient. 請求の範囲第３６又は３７項記載のペプチドからなる鎮痛剤。An analgesic comprising the peptide according to claim 36 or 37. 請求の範囲第３６又は３７項記載のペプチドを有効成分として含有する医薬又は食品。A medicine or food containing the peptide according to claim 36 or 37 as an active ingredient. 鎮痛剤である請求の範囲第３９項記載の医薬又は食品。40. The pharmaceutical or food according to claim 39, which is an analgesic. 配列表の配列番号２５、２６、２７、２８、２９、３０、３１又は３２で示されるアミノ酸配列を有するペプチド、或いは該アミノ酸配列中の１若しくは複数のアミノ酸が置換し若しくは欠失し、又は該アミノ酸配列に１若しくは複数のアミノ酸が挿入され若しくは付加されたアミノ酸配列を有するペプチドであって、中枢神経系機能促進効果を有するペプチド。A peptide having the amino acid sequence represented by SEQ ID NO: 25, 26, 27, 28, 29, 30, 31, or 32 in the sequence listing, or one or more amino acids in the amino acid sequence are substituted or deleted, or A peptide having an amino acid sequence in which one or more amino acids are inserted or added to the amino acid sequence, and having a CNS function promoting effect. 配列表の配列番号２５、２６、２７、２８、２９、３０、３１又は３２で示されるアミノ酸配列を有するペプチドを有効成分とする請求の範囲第４１項記載のペプチド。The peptide according to claim 41, comprising a peptide having an amino acid sequence represented by SEQ ID NO: 25, 26, 27, 28, 29, 30, 31, or 32 in the sequence listing as an active ingredient. 請求の範囲第４１又は４２項記載のペプチドからなる中枢神経系機能促進剤。A central nervous system function promoter comprising the peptide according to claim 41 or 42. 請求の範囲第４１又は４２項記載のペプチドを有効成分として含有する医薬又は食品。A medicine or food containing the peptide according to claim 41 or 42 as an active ingredient. 中枢神経系機能促進剤である請求の範囲第４４項記載の医薬又は食品。45. The pharmaceutical or food according to claim 44, which is a central nervous system function promoter.
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US6030804A (en) * 1995-06-06 2000-02-29 Human Genome Sciences, Inc. Polynucleotides encoding G-protein parathyroid hormone receptor HLTDG74 polypeptides
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