JP2019508488A - メラニン生成促進活性を示すペプチド及びその用途 - Google Patents
メラニン生成促進活性を示すペプチド及びその用途 Download PDFInfo
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- JP2019508488A JP2019508488A JP2018560420A JP2018560420A JP2019508488A JP 2019508488 A JP2019508488 A JP 2019508488A JP 2018560420 A JP2018560420 A JP 2018560420A JP 2018560420 A JP2018560420 A JP 2018560420A JP 2019508488 A JP2019508488 A JP 2019508488A
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- peptide
- melanin
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- amino acid
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Classifications
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- C07K7/04—Linear peptides containing only normal peptide links
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- 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
- C07K14/475—Growth factors; Growth regulators
- C07K14/495—Transforming growth factor [TGF]
-
- 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
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/0004—Oxidoreductases (1.)
- C12N9/0071—Oxidoreductases (1.) acting on paired donors with incorporation of molecular oxygen (1.14)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y114/00—Oxidoreductases acting on paired donors, with incorporation or reduction of molecular oxygen (1.14)
- C12Y114/18—Oxidoreductases acting on paired donors, with incorporation or reduction of molecular oxygen (1.14) with another compound as one donor, and incorporation of one atom of oxygen (1.14.18)
- C12Y114/18001—Tyrosinase (1.14.18.1)
Landscapes
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
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- Public Health (AREA)
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- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Wood Science & Technology (AREA)
- Biophysics (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Birds (AREA)
- Immunology (AREA)
- Microbiology (AREA)
- Biomedical Technology (AREA)
- Biotechnology (AREA)
- Toxicology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cosmetics (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
合成例1:ペプチドの合成
クロロトリチルクロライドレジン(Chloro trityl chloride resin; CTL resin, Nova biochem Cat No. 01−64−0021)700mgを反応容器に入れてメチレンクロライド(MC)10mlを加えて3分間撹拌した。溶液を除去し、ジメチルホルムアミド(DMF)10mlを入れて3分間撹拌した後、また溶媒を除去した。反応器に10mlのジクロロメタン溶液を入れてFmoc−Asp(OtBu)−OH(Bachem、Swiss)200mmole及びジイソプロピルエチルアミン(DIEA)400mmoleを入れた後、撹拌してよく溶かして、1時間の間撹拌しながら反応させた。反応後、洗浄し、メタノールとDIEA(2:1)をDCM(dechloromethane)に溶かして10分間反応させ、過量のDCM/DMF(1:1)で洗浄した。溶液を除去し、ジメチルホルムアミド(DMF)を10ml入れて3分間撹拌した後、また溶媒を除去した。脱保護溶液(20%のピペリジン(Piperidine)/DMF)10mlを反応容器に入れて10分間常温で撹拌した後、溶液を除去した。同量の脱保護溶液を入れて、また10分間反応を維持した後、溶液を除去し、各々3分ずつDMFで2回、MCで1回、DMFで1回洗浄してAsp(OtBu)−CTL Resinを製造した。新たな反応器に10mlのDMF溶液を入れてFmoc−Glu(OtBu)−OH(Bachem、Swiss)200mmole、HoBt 200mmole、及びBop 200mmoleを入れた後、撹拌してよく溶かした。反応器に400mmole DIEAを分画に2回に亘って入れた後、全ての固体が溶けるまで最小限5分間撹拌した。溶かしたアミノ酸混合溶液を脱保護されたレジンがある反応容器に入れて1時間の間常温で撹拌しながら反応させた。反応液を除去し、DMF溶液で3回5分ずつ撹拌した後、除去した。反応レジンを少量取ってカイザーテスト(Nihydrin Test)を用いて反応程度を点検した。脱保護溶液で前記と同様に2回脱保護反応させてGlu(OtBu)−Asp(OtBu)−CTL Resinを製造した。DMFとMCで十分に洗浄し、もう一度カイザーテストを遂行した後、前記と同様に以下のアミノ酸付着実験を遂行した。選ばれたアミノ酸配列に基づいてFmoc−Ile−OH、Fmoc−Lys(Boc)−OH、Fmoc−Arg(Pbf)−OH、Fmoc−Arg(Pbf)−OH、Fmoc−Trp−OH、及びFmoc−Arg(Pbf)−OHの順に連鎖反応させた。Fmoc−保護基を脱保護溶液で10分ずつ2回反応させた後、よく洗浄して除去した。無水酢酸とDIEA、HoBtを入れて1時間の間アセチル化を遂行した後、製造されたペプチジルレジンをDMF、MC、及びメタノールで各々3回を洗浄し、窒素空気をゆっくり流して乾燥した後、P2O5下で真空に減圧して完全に乾燥した後、脱漏溶液[トリフルロ化酢酸(Trifluroacetic acid)95%、蒸留水2.5%、チオアニソール(Thioanisole)2.5%]30mlを入れた後、常温で時々揺らしながら2時間反応を維持した。フィルタリングを行ってレジンを濾して、レジンを少量のTFA溶液で洗浄した後、母液と合せた。減圧を用いて全体ボリュームが半分位残るように蒸留し、50mlの冷たいエーテルを加えて沈殿を誘導した後、遠心分離して沈殿を集めて、もう2回冷たいエーテルで洗浄した。母液を除去し、窒素下で十分に乾燥して精製前Arg−Trp−Arg−Arg−Lys−Ile−Glu−Asnペプチド1を0.65g合成した(収率:92.0%)。分子量測定機を用いて測定時、分子量1157.3(理論値:1157.33)を得ることができた。また、配列番号2のアミノ酸配列からなるペプチドも前記のような方法により合成を進行した。
6−ウェル培養用平板にメラニン形成細胞(B16F10細胞株)を37℃培養器で24時間培養した後、各板の培地を除去し、新たな培地に取替後、本ペプチドを濃度別に処理した。72時間の間培養した後、培養液を除去し、細胞を剥がした後、1.5mlチューブに移して13,000rpmで3分間遠心分離して上層液を除去し、細胞ペレットを回収してメラニンを観察した。細胞ペレットを2M NaOH 150ulずつ入れて60℃で30分間細胞内メラニンを溶解させた。96−ウェル平板の各ウェルに溶解させて得た上層液を100ulずつ入れて490nmで吸光度を測定して、図1a及び図1bに示した。
黒色腫細胞株(B16F10)細胞を6−ウェル培養用平板に24時間培養し、濃度別ペプチドを処理して72時間培養した。氷の上に6−ウェル培養用平板を上げて、冷たいPBSで洗浄した後、1% Triton X−100が含まれた0.1Mリン酸ナトリウムバッファ(pH6.8、溶解バッファ)を300uL入れて、細胞を1.5mLチューブに集めて−270℃に急速冷凍させた後、解凍させる反応を5回繰り返して細胞膜を破壊した。13,000rpmで20分間遠心分離した後、上層液を他の1.5mLチューブに集めて、この試料のタンパク質を定量した。試料のタンパク質濃度が同じ濃度になるように希薄して96−ウェル培養用平板に3個のウェルずつ株分けし、10mM L−dopa 20uLを添加して37℃で1時間培養後、475nmで吸光度を測定した。
メラニン形成細胞(B16F10細胞株)を6−ウェル培養用平板に24時間培養後、ペプチドを濃度別に処理した。72時間の間培養された細胞のRNA抽出後、cDNAを製作した。メラニン形成に関与する因子であるMITF及びチロシナーゼに対する各々の特異的なプライマーを用いてPCRして各遺伝子の発現変化を観察して、その結果を図3a及び図3bに示した。
メラニン形成細胞(B16F10細胞株)を6−ウェル培養用平板に24時間培養後、本ペプチドを濃度別に処理した。72時間の間培養した後、細胞を溶解してメラニン形成に関与する因子であるMITF及びチロシナーゼの発現を特異的な抗体(2種類全てSantacruz biotechnology、USA)を用いてウェスタンブロットにより確認して、その結果を図4a及び図4bに示した。
メラニン形成細胞(B16F10細胞株)を6−ウェル培養用平板に24時間培養後、本ペプチドを濃度別に処理した。72時間の間細胞を培養した後、細胞を溶解してメラニン形成に関与する信号伝達物質であるCREBのリン酸化程度を特異的な抗体(cell Signaling Technology、USA)を用いてウェスタンブロットにより確認して、その結果を図5に示した。
Claims (9)
- 配列番号1または2のアミノ酸配列からなるメラニン生成促進活性を示す、ペプチド。
- 前記ペプチドは、チロシナーゼ(tyrosinase)の活性を増加させることを特徴とする、請求項1に記載のペプチド。
- 前記ペプチドは、MITF(Microphthalmia−associated transcription factor)及びTRP1(Tyrosinase−related protein 1)からなる群から選択されるメラニン合成関連因子の発現を増加させることを特徴とする、請求項1に記載のペプチド。
- 前記ペプチドは、チロシナーゼの発現を増加させることを特徴とする、請求項1に記載のペプチド。
- 前記ペプチドは、CREB(cAMP response element−binding protein)のリン酸化を増加させることを特徴とする、請求項1に記載のペプチド。
- 配列番号1のアミノ酸配列からなるペプチド及び配列番号2のアミノ酸配列からなるペプチドからなる群から選択された1種以上のペプチドを有効成分として含む、メラニン低色素症の予防または治療用薬剤学的組成物。
- 前記メラニン低色素症は、白斑症、白色症、脱色素母斑、白色粃糠疹、白癜、炎症後脱色症、斑状硬皮症、部分白皮症、特発性滴状低色素症、または点状白皮症であることを特徴とする、請求項7に記載のメラニン低色素症の予防または治療用薬剤学的組成物。
- 配列番号1のアミノ酸配列からなるペプチド及び配列番号2のアミノ酸配列からなるペプチドからなる群から選択された1種以上のペプチドを有効成分として含む、メラニン低色素症の予防または改善用化粧品組成物。
- 前記メラニン低色素症は、白斑症、白色症、脱色素母斑、白色粃糠疹、白癜、炎症後脱色症、斑状硬皮症、部分白皮症、特発性滴状低色素症、または点状白皮症であることを特徴とする、請求項8に記載のメラニン低色素症の予防または改善用化粧品組成物。
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