JP2012523453A - 形質転換成長因子の活性を有するペプチド及びその用途 - Google Patents
形質転換成長因子の活性を有するペプチド及びその用途 Download PDFInfo
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Abstract
【選択図】図4
Description
(i)本発明のペプチドは、ヒトTGF−β由来で、天然のヒトTGF−βと類似した機能又は作用を有する。
(ii)本発明のペプチドは、天然TGF−βより安定性に優れており、天然TGF−βの大きい分子量による問題点を改善することができる。
(iii)本発明のペプチドは、TGF−βが適用される多様な疾患又は状態の治療又は改善に利用でき、特に、皮膚美白及びシワの改善に著しい効能を発揮する。
クロロトリチルクロライドレジン(Chloro trityl chloride resin: CTL resin, Novabiochem Cat No. 01−64−0021)500mgを反応容器に入れ、メチレンクロライド(MC)10mlを加え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、Fmoc−Gln(trt)−OH(Novabiochem)200μmole及びDIEA(diisopropylethylamine)400μmoleを入れた後、攪拌してよく溶かし、1時間攪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、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、Gln(trt)−CTLレジンを製造した。新しい反応器に10mlのDMF溶液を入れ、Fmoc−Thr(otbu)−OH(Novabiochem, 米国)200μmole、HoBt(N−Hydroxybenzotriazole)200μmole及びBop 200μmoleを入れた後、攪拌してよく溶解させた。反応器に400μmole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調べた。脱保護溶液で上記と同様に2回脱保護反応し、Thr(otbu)−Gln(trt)−CTLレジンを製造した。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、図1のように選定されたアミノ酸配列に基づき、Fmoc−Asp(otbu)、Fmoc−Leu、Fmoc−Ser(tBu)、Fmoc−Trp(boc)、Fmoc−Ile、Fmoc−Thr(tBu)、Fmoc−Asp(otbu)、Fmoc−Gly、Fmoc−Arg(pbf)、Fmoc−Glyの順に連鎖反応を行った。製造されたペプチジルレジンは、同様の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(Thioanisole)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、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、更に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−Gly−Arg−Gly−Asp−Tyr−Ile−Trp−Ser−Leu−Asp−Thr−Gln−OH(配列番号2)のペプチド0.144g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1411.0(理論値1410.5)が得られた。
精製された配列番号2のペプチドの安定性を確認するために、10μg/mlとなるようにペプチドを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、40℃で静置した。40℃に静置された溶液を、0日目、1日目、10日目、25日目、50日目、75日目、及び100日目にサンプリングし、NIH−3T3細胞(Korean Cell Line Bank)に対するMTTアッセイ(Scudiero, D. A., et al. Cancer Res. 48:4827−4833(1988))を行って、残っているペプチドの残存量を測定した(図3)。
前記実施例から得られたペプチド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1で製造されたペプチドナノソームを含み、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1で製造されたペプチドナノソームを含み、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1で製造されたペプチドナノソームを含み、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1で製造されたペプチドナノソームを含み、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で合成した配列番号2のペプチドのメラニン色素の減少効果を測定するために、C57BL/6マウスの色素細胞(melanocyte)を培養した後、α−MSH(melanocyte stimulating hormone /Sigma、米国)でメラニン生成を誘発させた後、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、DMEM(Dulbecco’s modified Eagle’s media,Sigma)に10%牛胎児血清(fetal bovine serum,Sigma)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1×105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、対照群には何も処理せず溶媒のみを入れ、陽性対照群は、α−MSHを200μg/ml、そして他のディッシュには配列番号2ペプチドを1μg/mlと10μg/mlの濃度になるように処理をした。それぞれのディッシュは、試験物質を加えて3日間培養した。ここで試験物質は、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、同一な比率で混合したものである。遠心分離を通じて培養液を除去した後、細胞のメラニン生成量を肉眼で確認することができ、そのうち、10μg/ml濃度の処理群に対する結果が図4に示されている。図4から確認できるように、α−MSHを入れた群ではメラニン生成が急激に高くなったが、ペプチドを処理した群では、α−MSHを処理しなかった時と類似したメラニン生成を示した。これは、皮膚にメラニンの生成を誘発させる要因が適用された時、ペプチドがその活性を抑制し、皮膚のトーンを明るくすることができることがわかる。
実施例1で合成した配列番号2の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(韓国細胞株バンク)を1×105個程度接種して、3日間培養した。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、陰性対照群には何の処理もせず、陽性対照群には、α−MSHを200ng/mlの濃度で処理した。他のディッシュには、α−MSH 200μg/mlと共に、実施例で製造した配列番号2のペプチドをそれぞれ1μg/mlと10μg/mlの濃度で処理した。4日間培養後、細胞の様子を観察した後、細胞を収集し、リーシス緩衝液で処理して蛋白質を抽出した。抽出した蛋白質をBCA(bicinchonic acid)方法で定量した後、各群別に90μlの蛋白質溶液に10μlのL−DOPA(L−3,4−dihydroxyphenylalanine, Sigma)を入れ、37℃で30分間反応した後、405nm分光光度計で吸光度を測定して、チロシナーゼの活性を測定した。
α−MSHを処理してメラニン生成が誘発されたマウス黒色腫細胞において、TGF模倣ペプチドの美白活性をより確実に検証するために、TRP1(tyrosinase−related protein−1)、TRP2及びMITF(microphthalmia−associated transcription factor)のRNA生成を、逆転写重合酵素連鎖反応で観察した。
48時間培養したNIH3T3細胞に、合成した配列番号2のペプチドを1μg/ml又は10μg/mlの濃度で処理し、72時間経過後、皮膚シワ改善の標識であるプロコラーゲン及びフィブロネクチンの濃度を測定した。濃度測定は、プロコラーゲンELISAキット(Takara,日本)及びフィブロネクチンELISAキット(Chemicon,米国)を利用して行った。図9から確認できるように、本発明のペプチドは、線維芽細胞のプロコラーゲン生成を増加させた。特に、配列番号2のペプチドが優れたプロコラーゲン生成促進能を示した。また、図10から確認できるように、本発明のペプチドは、線維芽細胞のフィブロネクチン生成を増加させた。特に、配列番号2のペプチドが優れたフィブロネクチン生成促進能を示した。このことから、配列番号2のペプチドは、皮膚に処理時、非常に優れたシワ改善効能を奏するということがわかる。
本発明のペプチドに対する皮膚細胞の細胞内毒性があるかどうかを確認するために、Rizzinoらの方法(Rizzino, et al. Cancer Res., 48:4266(1988))を参照して、HaCat細胞(韓国細胞株バンク)、NIH3T3細胞(韓国細胞株バンク)及びB16F10細胞株(韓国細胞株バンク)を利用したSRB(Sulforhodamine B,Sigma)の比色法を利用して測定した。それぞれの細胞株を、10%FBS(fetal bovine serum)が含有されたEMEM(Eagle’s minimal essential media, Gibco)を添加した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1×105細胞になるように入れて、24時間37℃、7%CO2の条件下で培養した。24時間後、血清を完全に除去した同一の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ペプチドを水と10%DMSO(Dimethyl sulfoxide)に滅菌状態で溶解した後、10ng/ml、100ng/ml、1μg/ml、10μg/ml、及び100μg/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、PBSで1回洗浄した。洗浄溶液を除去した後、比色SRB溶液で処理し、PBSで十分洗浄した後、顕微鏡で各細胞を観察し、生存細胞の状態を観察して、紫外線590nmで吸光度を測定し、各細胞の生存状態を図11A〜11Cに示した。
Claims (12)
- 配列番号1で表されるアミノ酸配列を含むことを特徴とするTGF−β(Transforming growth factor−beta)模倣ペプチド。
- N−末端又はC−末端に、更に細胞付着アミノ酸配列が結合されている請求項1に記載のTGF−β模倣ペプチド。
- 細胞付着アミノ酸配列が、TGF−β模倣ペプチドのN−末端に結合されている請求項2に記載のTGF−β模倣ペプチド。
- 細胞付着アミノ酸配列が、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)又はLDVPS(Leu−Asp−Val−Pro−Ser)である請求項2に記載のTGF−β模倣ペプチド。
- 細胞付着アミノ酸配列が、RGD(Arg−Gly−Asp)である請求項4に記載のTGF−β模倣ペプチド。
- N−末端又はC−末端に、更にアセチル基、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、ポリエチレングリコール(PEG)及びアミノ酸からなる群から選択される保護基が結合されている請求項1に記載のTGF−β模倣ペプチド。
- N−末端又はC−末端に、更にアセチル基、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、ポリエチレングリコール(PEG)及びアミノ酸からなる群から選択される保護基が結合されている請求項2に記載のTGF−β模倣ペプチド。
- 保護基が、N−末端に結合されている請求項7に記載のTGF−β模倣ペプチド。
- TGF−β(Transforming growth factor−beta)活性を示す請求項1から8のいずれかに記載のペプチドを有効成分として含むことを特徴とするTGF−β−有効性(TGF−β−effective)の疾患又は状態(conditions)の予防又は治療用組成物。
- TGF−β−有効性疾患又は状態が、組織損傷、動脈硬化、傷(wound)、骨欠陥、リウマチ様関節炎、ぶどう膜炎、癌、シワの改善又は皮膚美白である請求項9に記載の組成物。
- TGF−β(Transforming growth factor−beta)活性を示す請求項1から8のいずれかに記載のペプチドを有効成分として含む組成物を対象(subject)に投与する段階を含むことを特徴とするTGF−β−有効性(TGF−β−effective)の疾患又は状態(conditions)の予防又は治療方法。
- TGF−β−有効性の疾患又は状態が、組織損傷、動脈硬化、傷(wound)、骨欠陥、リウマチ様関節炎、ぶどう膜炎、癌、シワの改善又は皮膚美白である請求項11に記載の方法。
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