JP5378353B2 - Tgfp−capペプチド及びその用途 - Google Patents
Tgfp−capペプチド及びその用途 Download PDFInfo
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- JP5378353B2 JP5378353B2 JP2010503955A JP2010503955A JP5378353B2 JP 5378353 B2 JP5378353 B2 JP 5378353B2 JP 2010503955 A JP2010503955 A JP 2010503955A JP 2010503955 A JP2010503955 A JP 2010503955A JP 5378353 B2 JP5378353 B2 JP 5378353B2
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Description
一般式I
Ile-Trp-Ser-Leu-Asp-Thr-Gln-Tyr-細胞付着アミノ酸配列
前記一般式Iにおいて、前記細胞付着アミノ酸配列は、RGD(Arg-Gly-Asp), RGDS(Arg-Gly-Asp-Ser), RGDC(Arg-Gly-Asp-Cys), RGDV(Arg-Gly-Asp-Val), RGES(Arg-Gly-Glu-Ser), RGDSPASSKP(Arg-Gly-Asp-Ser-Pro-Ala-Ser-Ser-Lys-Pro), GRGDS(Gly-Arg-Gly-Asp-Ser), GRADSP (Gly-Arg-Ala-Asp-Ser-Pro), KGDS(Lys-Gly-Asp-Ser), GRGDSP (Gly-Arg-Gly-Asp-Ser-Pro), GRGDTP(Gly-Arg-Gly-Asp-Thr-Pro), GRGES (Gly-Arg-Gly-Glu-Ser), GRGDSPC(Gly-Arg-Gly-Asp-Ser-Pro-Cys), GRGESP (Gly-Arg-Gly-Glu-Ser-Pro), SDGR(Ser-Asp-Gly-Arg), YRGDS (Tyr-Arg-Gly-Asp-Ser), GQQHHLGGAKQAGDV (Gly-Gln-Gln-His-His-Leu-Gly-Gly-Ala-Lys-Gln-Ala-Gly-Asp-Val), GPR (Gly-Pro-Arg), GHK(Gly-His-Lys), YIGSR(Tyr-Ile-Gly-Ser-Arg), PDSGR(Pro-Asp-Ser-Gly-Arg), CDPGYIGSR(Cys-Asp-Pro-Gly-Tyr-Ile-Gly-Ser-Arg), LCFR(Leu-Cys-Phe-Arg), EIL(Glu-Ile-Leu), EILDV(Glu-Ile-Leu-Asp-Val), EILDVPST(Glu-Ile-Leu-Asp-Val-Pro-Ser-Thr), EILEVPST(Glu-Ile-Leu-Glu-Val-Pro-Ser-Thr), LDV(Leu-Asp-Val)またはLDVPS(Leu-Asp-Val-Pro-Ser)である。
一般式II
Ile-Trp-Ser-Leu-Asp-Thr-Gln-Tyr-リンカー-細胞付着アミノ酸配列
前記一般式IIにおいて、前記細胞付着アミノ酸配列は、前記一般式Iと同一である。
一般式III
Ile-Trp-Ser-Leu-Asp-Thr-Gln-Tyr-Gly(n)-Arg-Gly-Asp
前記一般式IIIにおいて、nは2〜8の整数を示す。
(i)本発明のTGFP-CAPペプチドは、優れた抗血管新生活性を示す。
(ii)本発明のTGFP-CAPペプチドは、皮膚からメラニン形成を効果的に遮断することにより美白効能を示す。
(iii)本発明のペプチドは、安定性が天然TGF-β1と比較して非常に優れており、皮膚透過度に非常に優れている。
(iv)上述の本発明のペプチドの優れた活性及び安定性は、医薬、医薬外品及び化粧品に非常に有利に適用できるようにする
NH2-Ile-Trp-Ser-Leu-Asp-Thr-Gln-Tyr-Gly(n)-Arg-Gly-Asp-OH 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分間攪拌した。溶液を除去し、ジメチルホルムアミド(DMF)を10ml入れて3分間攪拌した後、再び溶媒を除去した。反応器に10mlのメチレンクロライド溶液を入れて、Fmoc-Asp(otbu)-OH 200mmole及びDIEA 400mmoleを入れた後、攪拌してよく溶かして、1時間攪拌しながら反応させた。反応後、洗浄して、メタノールとDIEA(2:1)をMCに溶解してレジンと10分間反応した後、過量のMC/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分間攪拌した後、再び溶媒を除去した。脱保護溶液(20%のピペリジン/DMF)10mlを反応容器に入れて、10分間常温で攪拌した後、溶液を除去した。同量の脱保護溶液を入れて、再び10分間反応を維持した後、溶液を除去し、DMFで2回、MCで1回、再びDMFで3分間1回洗浄して、Gly-CTLレジンを製造した。新しい反応器に10mlのDMF溶液を入れて、Fmoc-Gly-OH(Novabiochem, 米国)200mmole、HoBt 200mmole及びBop 200mmoleを入れた後、攪拌してよく溶解させた。反応器に400mmoleのDIEAを分画で2回にかけて入れて、全ての固体が溶けるまで少なくとも5分間攪拌した。溶解されたアミノ酸混合溶液を、脱保護されたレジンが入っている反応容器に入れて、1時間常温で攪拌しながら反応させた。反応液を除去し、DMF溶液で5分間ずつ3回攪拌した後、未反応溶媒を除去した。反応レジンを少量取って、カイザーテスト(Ninhydrine test)を利用して反応程度を点検した。脱保護溶液で上記と同様に2回脱保護反応し、Gly-Asp(tBu)-CTL resinを製造した。DMFとMCで十分洗浄し、再びカイザーテストを行った後、上記と同様に下記のアミノ酸付着実験を行った。即ち、本発明で選定されたアミノ酸配列に基づき、Fmoc-Arg(pbf), Fmoc-Gly(n回), Fmoc-Tyr(tBu), Fmoc-Gln(trt), Fmoc-Thr(tBu), Fmoc-Asp(otbu), Fmoc-Leu, Fmoc-Ser(tBu), Fmoc-Trp(boc), Fmoc-Ileの順に連鎖反応を行った。但し、中間のGlyは、ペプチド別にそれぞれ2回反復から6回反復まで多様な残基数で合成を行い、合計5種のペプチジルレジンを製造した。製造されたペプチジルレジンは、同様な方法により脱保護してFmocを除去した後、DMF、MC及びメタノールでそれぞれ3回洗浄し、窒素空気を徐々に流して乾燥した後、P2O5下で真空に減圧して完全に乾燥し、ペプチジルレジンを準備した。製造されたレジンに脱漏溶液[トリフルオロ化酢酸(TFA)81.5%、蒸留水5%、チオアニソール5%、フェノール5%、EDT 2.5%及びTIS 1%]30mlを入れて、常温で時々振りながら2時間反応を維持した。フィルタリングでレジンを濾過し、レジンを少量のTFA溶液で洗浄した後、母液と合わせた。減圧を利用して、全体容量が半分ぐらい残るように蒸留して、50mlの冷たいエーテルを加えて沈澱を誘導した後、遠心分離して沈澱を集め、さらに2回冷たいエーテルで洗浄した。母液を除去して窒素下で十分乾燥し、精製前のNH2-Ile-Trp-Ser-Leu-Asp-Thr-Gln-Tyr-Gly(n)-Arg-Gly-Asp-OH 5種のペプチドを獲得した。即ち、前記アミノ酸配列において、リンカー役割をするGly残基の数が1〜5個の5種のペプチドを収得した。この中、NH2-Ile-Trp-Ser-Leu-Asp-Thr-Gln-Tyr-Gly-Gly-Arg-Gly-Asp-OHの場合は、約0.87gを収得し、分子量測定器(Perseptive Pioneer DE-STR ABI, 米国)を利用して、分子量1467.9(理論値1467.5)が得られた。下記の実施例は、リンカーとしてGly残基が2個であるペプチドを利用して行った。図1は、合成して精製したペプチドを、HPLCを通じて分析した結果である。
実施例1で製造及び精製されたトリデカペプチド、即ち、NH2-Ile-Trp-Ser-Leu-Asp-Thr-Gln-Tyr-Gly-Gly-Arg-Gly-Asp-OHの安定性を確認するために、10μg/mlとなるように、トリデカペプチドを50mM Tris-HCl(pH 8.0)緩衝溶液に溶解した。対照群として、1μg/mlの濃度で大腸菌から生産された組換えTGF-β1(Sigma)を類似緩衝溶液に用意した。用意した溶液をガラスバイアルに入れて、37℃で静置した。37℃で静置された溶液を、0、1、10、25、50、75、そして100日目にサンプリングして、NIH-3T3 cell (Korean Cell Line Bank)に対するMTT分析(Scudiero, D. A., et al. Cancer Res. 48:4827-4833(1988))を行って、ペプチドとTGF-β1の活性を測定した(図2)。この時、0日のサンプル活性を100%として基準した。
前記実施例から得られたトリデカペプチド50mgを正確に秤量した後、蒸留水500mlで十分に攪拌して溶解した。ペプチド溶液を、レシチン5g、オレイン酸ナトリウム(sodium oleate)0.3ml、エタノール50ml及び少量の油相と共に混合した後、総量が1Lとなるように蒸留水で調節した後、マイクロ流動化装置(microfluidizer)を利用して高圧で乳化し、大きさ100nm程度のナノソームを製造した。製造されたナノソームは、最終濃度が約50ppmであって、化粧品製造用に使用した。
前記実施例3で製造されたトリデカペプチド含有ナノソームを含み、下記組成からなる柔軟化粧水を、一般的な化粧水製造方法により製造した。
前記実施例3で製造されたトリデカペプチド含有ナノソームを含み、下記組成からなる栄養クリームを、一般的な栄養クリームの製造方法により製造した。
前記実施例3で製造されたトリデカペプチド含有ナノソームを含み、下記組成からなる栄養化粧水を、一般的な化粧水製造方法により製造した。
前記実施例3で製造されたトリデカペプチド含有ナノソームを含み、下記組成からなるエッセンスを、一般的なエッセンス製造方法により製造した。
実施例1で製造したペプチドのメラニン色素の減少効果を測定するために、マウスの色素細胞(melanocyte)を培養した後、α-MSH(melanocyte stimulating hormone /Sigma、米国)を添加した後、ペプチドを濃度別に処理して、メラニン生成抑制効果を測定した。マウスの色素細胞は、C57BL/6マウス由来のもので、DMEM(Dulbecco's modified Eagle's media)に10%牛胎児血清(fetal bovine serum)を添加した培地で37℃, 5% CO2条件で培養した。24-ウェルプレートに1 x 105 細胞/ウェル(cells/well)の濃度で細胞を培養し、細胞の付着を確認した後、細胞培養液に一定な濃度の試験物質を加えて、3日間培養した。ここで試験物質は、下記表5の組成物のそれぞれの成分を培地溶媒に溶解した後、プロピレングリコール:エタノール:精製水の比率が5:3:2である混合溶媒に溶解させて試験濃度に希釈して、同一な比率で混合したものである。培養液を除去し、PBSで洗浄した後、1N水酸化ナトリウムで細胞を溶かし、400nmで吸光度を測定した後、メラニン生成抑制率を計算し、その結果を図3に示した(Dooley方法)。
実施例1で合成したトリデカペプチドと形質転換成長因子の美白活性を検証するために、メラニン生成因子であるα-MSHを処理した後のメラニン生成抑制能を調べた。B16F10細胞(韓国細胞株銀行)を1x105個程度培養ディッシュに接種して、三日間37℃, 5% CO2条件でDMEM(Sigma 米国)培地で培養した。細胞が定着された後、2%血清が含有された培地に入れ替えた。細胞培養液に一定な濃度の試験物質を加えて、四日間37℃, 5% CO2条件で培養した。ここで試験物質は、下記表6の組成物のそれぞれの成分を培地溶媒に溶解した後、プロピレングリコール:エタノール:精製水の比率が5:3:2である混合溶媒に溶解させて試験濃度に希釈して、同一な比率で混合したものである。
実施例1で合成したトリデカペプチドと形質転換成長因子の美白活性を検証するために、ERK抑制活性を有する標識物質であるPD98059(Sigma, USA)を通じてERKの活性を抑制した後、これを克服する活性を観察した。まず6-ウェルの細胞培養ディッシュにB16F10細胞を1 x 105 個程度接種して、三日間37℃, 5% CO2 条件でDMEM培地で培養した。細胞が定着された後、2%血清が含有された培地に入れ替えた。陰性対照群には何の処理もせず、他の二つの培養ディッシュには、それぞれ形質転換成長因子1ng/mlと実施例1で製造したトリデカペプチドを30μg/mlの濃度でそれぞれ処理した。一方、他の三つのディッシュには、陽性対照群として、10μMのERK抑制因子のPD98059(ERK蛋白質がリン酸化されることを妨害する物質)を処理した。この中、二つのディッシュには、一時間後、形質転換成長因子1ng/mlと実施例1で製造したトリデカペプチドを30μg/mlの濃度でそれぞれ処理した後、四日間培養して、顕微鏡を通じて細胞の形態を観察した。
健康な5週齢の雄性Balb/Cマウス(中央実験動物, 韓国)の背中部位の毛を除毛した後、培養したB16F10黒色腫(韓国細胞株銀行)をそれぞれ200万細胞ずつ、背中の2ヶ所に注入した。正常食餌をしてマウスを三日間飼育した後から、黒色腫部位が黒く腫れてくることを観察することができた。同じ程度に腫れている二つの部位に、1ヶ所には対照群としてPBSを、他の1ヶ所には約100μgのトリデカペプチドを、一日一回ずつ投与した。
本発明のペプチドに対し、角質細胞、線維芽細胞及び黒色腫細胞に対する毒性があるかどうかを確認するために、Rizzinoらの方法(Cancer Res., 48:4266(1988))を参照して、HacaT, NIH3T3及びB16F10細胞株を利用したSRB(Sulforhodamine B)のひ比色法を利用して測定した。HacaT, NIH3T3及びB16F10細胞株(韓国細胞株銀行)を、それぞれ100% FBS(fetal bovine serum)が含有されたEMEM(Eagle's minimal essential media, Gibco, U.S.A.)が入っている250ml容量の組織培養用フラスコを利用して培養した。培養されたHacaT, NIH3T3及びB16F10細胞株を、0.25%トリプシン溶液で培養容器の底から離した後、遠心分離して、細胞沈殿物のみを集めた。これを、FBSが含有されていないEMEM培養液に再び懸濁した後、96-ウェル組織培養用平板に、各ウェル当たり1 x 105 細胞になるように入れて、24時間37℃, 7%CO2 条件下で培養した。24時間後、血清を完全に除去した同一な培養液に培地を入れ替えた後、標準を取るための空試料とトリデカペプチドを水と10% DMSOに滅菌状態で溶解した後、500pg/ml, 10ng/ml, 1μg/ml, 100μg/ml及び200μg/mlの濃度で、上記と同一条件で72時間培養した。培養が完了した後、培養上澄み液を除去して、PBSで1回洗浄した。洗浄溶液を除去した後、比色SRB溶液(Sigma, USA)で処理し、PBSで十分洗浄した後、顕微鏡で細胞を観察し、生存細胞の状態を観察して、590nmで吸光度を測定し、細胞の生存状態を測定した。図9から分かるように、低濃度から高濃度まで投与したペプチドによる細胞数の減少は全く観察されず、細胞の顕微鏡的な観察においても、特別な変化が観察されなかった。このことから、本ペプチドは、皮膚関連細胞の毒性が全くないことが分かり、本ペプチドを皮膚に処理しても、皮膚細胞に大きい影響を及ぼさないことが分かった。
Claims (4)
- TGF-β1(transforming growth factor-β1)由来のアミノ酸配列、リンカー及び細胞付着アミノ酸配列を含み、前記TGF-β1由来のアミノ酸配列は、配列番号1に記載のアミノ酸配列から構成されて、下記の一般式IIIで表されるTGFP-CAPペプチド:
一般式III
Ile-Trp-Ser-Leu-Asp-Thr-Gln-Tyr-Gly(n)-Arg-Gly-Asp
前記一般式III において、nは2〜8の整数を示す。 - 前記ペプチドのN−末端及びC−末端にあるアミノ酸残基の少なくとも一つは、アセチル基、フルオレニルメトキシカルボニル基、ホルミル基、パルミトイル基、ミリスチル基、ステアリル基及びポリエチレングリコール(PEG)からなる群から選択される保護基が結合されていることを特徴とする、請求項1に記載のペプチド。
- 請求項1または2に記載のペプチドを有効成分として含む癌の予防または治療用薬剤学的組成物。
- 請求項1または2に記載のペプチドを有効成分として含む皮膚美白用組成物。
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EP1538164A1 (en) * | 2003-12-04 | 2005-06-08 | Vectron Therapeutics AG | RGD targeting moiety its production and use |
WO2006012355A2 (en) * | 2004-06-28 | 2006-02-02 | University Of Maryland, Baltimore | Radiolabeled nanohybrids targeting solid tumor neovasculature and method of using same |
CN104072614B (zh) * | 2005-07-08 | 2017-04-26 | 生物基因Ma公司 | 抗-αvβ6 抗体及其用途 |
EP1919933A2 (en) * | 2005-08-16 | 2008-05-14 | Copenhagen University | Gdnf derived peptides |
US8420605B2 (en) * | 2005-09-07 | 2013-04-16 | The University Of Strathclyde | Hydrogel compositions |
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- 2007-09-12 WO PCT/KR2007/004405 patent/WO2008130082A1/en active Application Filing
- 2007-09-12 CN CN200780053207.3A patent/CN101687935B/zh active Active
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WO2008130082A1 (en) | 2008-10-30 |
US8969296B2 (en) | 2015-03-03 |
US20100160238A1 (en) | 2010-06-24 |
EP2142572B1 (en) | 2015-07-29 |
ES2550145T3 (es) | 2015-11-04 |
EP2142572A4 (en) | 2010-11-24 |
KR100879239B1 (ko) | 2009-01-16 |
CN101687935B (zh) | 2015-04-22 |
EP2142572A1 (en) | 2010-01-13 |
CN101687935A (zh) | 2010-03-31 |
KR20080094296A (ko) | 2008-10-23 |
JP2010524920A (ja) | 2010-07-22 |
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