JP2019526530A - 新規ペプチド及びその用途 - Google Patents
新規ペプチド及びその用途 Download PDFInfo
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- JP2019526530A JP2019526530A JP2018565353A JP2018565353A JP2019526530A JP 2019526530 A JP2019526530 A JP 2019526530A JP 2018565353 A JP2018565353 A JP 2018565353A JP 2018565353 A JP2018565353 A JP 2018565353A JP 2019526530 A JP2019526530 A JP 2019526530A
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- brain
- peptide
- beta amyloid
- disease
- present
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
- C07K5/10—Tetrapeptides
- C07K5/1021—Tetrapeptides with the first amino acid being acidic
-
- C—CHEMISTRY; METALLURGY
- 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Health & Medical Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
下記表1に記載したペプチドをAnyGen(株)(AnyGen Co.,Ltd.,韓国)に依頼して製造した。具体的にFmoc(9−fluorenyl−methoxycarbonyl)化学的性質を用いたソリッドフェーズ法(solid phase method)によって合成した。より具体的には、固相樹脂(Wang resin;Sigma−aldrich社)0.55mmol/gを使用してペプチドのC−末端を固相樹脂に結合して実施した。Fmoc−Phe−OHアミノ酸のカップリング(coupling)は、O−Benzotriazole−N,N,N’,N’−tetramethyl−uronium−hexafluoro−phosphate(HBTU)とともに実施された。アミノ酸の側鎖はtert−butylとtert−butyloxycarbonylで保護した。保護基の除去(Deprotection)とレジン(resin)での分離は、トリフルオロ酢酸(trifluoroacetic acid)と水を95:5(v/v)の割合で混合した溶液を使用して室温で3時間実施した。粗(Crude)ペプチドは、ジエチルエーテル(diethylether)で繰り返して洗浄した後、真空乾燥してShimadzu 5 um Shimpak ODS C18 column(20x250mm)を用いて逆相高速液体クロマトグラフィー{reverse−phase HPLC;RP−HPLC}方法により精製した。精製されたペプチドは、Shimpak 5 um ODS C18 column(4.6x250mm)を用いて分析用逆相高速液体クロマトグラフィー(analytical RP−HPLC)方法により確認した。合成されたペプチドの分子量は、マトリックス支援レーザー脱離イオン化マススペクトルメータ{matrix−assisted laser desorption ionization(MALDI)−mass spectrometer}(Axima CFR、Kratos Analytical、Manchester、UK)を用いて確認した。
[表1]
実施例1のペプチドが血中のベータアミロイド1−42の脳内流入を抑制することを実験により確認した。具体的には、実施例1のペプチドがアルツハイマー病の原因の一つであるベータアミロイド1−42の脳内への流入を阻害する効果を確認するために、ベータアミロイド1−42(American Peptide Company、Sunnyvale、CA、USA)1mgにヘキサフルオロイソプロパノ−ル(Hexafluoroisopropanol:HFIP)2ml処理後に常温で3日間放置し、100μLずつチューブに分注した。Speed vacuumを用いてヘキサフルオロイソプロパノ−ル(HFIP)を蒸発させた後、分注した一つのチューブ(tube)に無水DMSO溶液{anhydrous DMSO(dimethyl sulfoxide)}を10μL入れて十分に溶かした後、リン酸緩衝生理食塩水(PBS;phosphate buffer saline)400μLを追加して最終的に25uMのベータアミロイド1−42溶液になるように準備した。
実施例1のペプチドの学習及び記憶回復効果を実験により確認した。具体的には、実施例1のペプチドがアルツハイマー病の症状の一つである学習能力及び記憶力の低下を抑制する効果を確認するために、遺伝子組み換えによりSwedish変異(Swedish mutation)があるベータアミロイド前駆タンパク質APP(APPsw;アミロイド突然変異)の人間由来遺伝子とγセクレターゼであるPS1遺伝子のエクソン−9欠損形態の人間由来遺伝子とが脳中に過量発現するようにして人間のアルツハイマー病を誘発させた30週齢のダブルトランスジェニックマウス{Double Transgenic mouse(DTgマウス)、Jackson Laboratory、米国}モデルを用いた実験を実施した。
%自発的交替行動量={(実際交差回数)/(全体交差回数−2)}x100
<動物モデルを用いた学習及び記憶回復効果の確認>実験において総13週間の投与期間が終了した動物モデルを用いてバイオマーカー変化効果を確認する実験を実施した。総13週間の腹腔投与が終了した動物モデルを二酸化炭素(CO2)を用いて安楽死させた後、直ちに脳を摘出した。脳を摘出する時、傷をつけないように脳全体を取り出した後生理食塩水を用いて軽く洗浄した。手術用メスを用いて半球を分離して左半球は準備したEPチューブ(EpPendorf tube)に入れた後、液体窒素で急速冷却させて次の実験時まで摂氏−80度のディープフリーザー(deep freezer)に保管した。
実施例1に対する以上の実験結果に基づいて、実施例1とともに実施例2及び比較例1ないし2のベータアミロイド1−42の脳内流入抑制効果の有無を確認するための実験を実施した。
[表2]
下記の方法により、実施例1と実施例2のペプチドがRAGEと結合することを確認することで、ベータアミロイドとRAGEとの結合が抑制されてベータアミロイドの脳内流入が抑制されることを確認した。
実施例1または実施例2と同様の方法により製造したペプチド500mgを生理食塩水に溶解させて溶液10mlを作る。作られた溶液は、注射剤用アンプルに充填して製造例1または製造例2の注射液剤を製造する。
Claims (5)
- 配列番号1のアミノ酸配列または配列番号2のアミノ酸配列からなるペプチド、または薬学的に許容可能なその塩。
- 請求項1のペプチドまたは薬学的に許容可能なその塩を含む、ベータアミロイドの脳内流入抑制剤。
- 請求項1のペプチドまたは薬学的に許容可能なその塩を含む、アルツハイマー病(Alzheimer’s disease)、認知症、パーキンソン(Parkinson)病、ハンチントン(Huntington)病、または脳内炎症の中から選ばれた一つ以上の治療または予防用薬学組成物。
- 前記アルツハイマー病(Alzheimer’s disease)、前記認知症、前記パーキンソン(Parkinson)病、前記ハンチントン(Huntington)病、または前記脳内炎症の中から選ばれた一つ以上は、脳内のベータアミロイド沈着によるものである請求項3に記載の薬学組成物。
- 前記治療または予防は、ベータアミロイドの脳内流入抑制によるものである請求項3に記載の薬学組成物。
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CA2576768A1 (en) | 2004-08-11 | 2006-03-23 | Wisconsin Alumni Research Foundation | Method of reducing the effects of a.beta. and compositions therefore |
WO2007089616A2 (en) | 2006-01-26 | 2007-08-09 | The University Of Rochester | Inhibiting amyloid-beta peptide/rage interaction at the blood-brain barrier |
KR20110136504A (ko) | 2010-06-15 | 2011-12-21 | 울산대학교 산학협력단 | Rage 수용체 표적 펩타이드에 약물을 결합시킨 것을 특징으로 하는 약물 복합체 |
KR101029705B1 (ko) * | 2010-06-30 | 2011-04-18 | (주)엔솔테크 | 신규 펩타이드 및 그 용도 |
KR101452235B1 (ko) | 2012-02-03 | 2014-10-22 | 서울대학교산학협력단 | 신규한 피리미딘계 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 포함하는 rage 수용체 관련 질환의 예방 또는 치료용 약학적 조성물 |
KR101595630B1 (ko) | 2013-01-18 | 2016-02-18 | 성균관대학교산학협력단 | Rage 단백질-베타아밀로이드 상호작용 억제제, 및 이를 유효성분으로 함유하는 베타아밀로이드 집적 관련 질환의 예방 또는 치료용 약학적 조성물 |
-
2017
- 2017-03-24 KR KR1020170037802A patent/KR101829631B1/ko active IP Right Grant
- 2017-03-24 JP JP2018565353A patent/JP6858325B2/ja active Active
- 2017-03-24 CN CN201780042801.6A patent/CN109476702B/zh active Active
- 2017-03-24 ES ES17831188T patent/ES2941363T3/es active Active
- 2017-03-24 US US16/309,557 patent/US10544190B2/en active Active
- 2017-03-24 EP EP17831188.2A patent/EP3489253B1/en active Active
- 2017-03-24 WO PCT/KR2017/003214 patent/WO2018016714A1/ko unknown
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CN109476702A (zh) | 2019-03-15 |
KR101829631B1 (ko) | 2018-02-19 |
JP6858325B2 (ja) | 2021-04-14 |
CN109476702B (zh) | 2022-04-29 |
KR20180010127A (ko) | 2018-01-30 |
US20190161517A1 (en) | 2019-05-30 |
EP3489253A4 (en) | 2019-12-18 |
WO2018016714A1 (ko) | 2018-01-25 |
EP3489253B1 (en) | 2023-03-01 |
US10544190B2 (en) | 2020-01-28 |
ES2941363T3 (es) | 2023-05-22 |
EP3489253A1 (en) | 2019-05-29 |
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