JP4971373B2 - インシュリン様成長因子−1の活性を有するペプチド及びその用途 - Google Patents
インシュリン様成長因子−1の活性を有するペプチド及びその用途 Download PDFInfo
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- JP4971373B2 JP4971373B2 JP2008558192A JP2008558192A JP4971373B2 JP 4971373 B2 JP4971373 B2 JP 4971373B2 JP 2008558192 A JP2008558192 A JP 2008558192A JP 2008558192 A JP2008558192 A JP 2008558192A JP 4971373 B2 JP4971373 B2 JP 4971373B2
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61K38/00—Medicinal preparations containing peptides
Description
(i)本発明のIGF−1模倣ペプチドは、天然のヒトIGF−1と同様な機能または作用をする。
(ii)本発明のペプチドは、その安定性が、天然IGF−1に比べ非常に優れており、また皮膚透過度が非常に高い。
(iii)したがって、本発明のペプチドを含む組成物は、IGF−1活性が要求される疾患または状態を治療、予防、または改善するのに非常に優れた効能を発揮する。
(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。
Gly-Phe-Tyr-Phe-Asn-Lys-Ala-Ala-Gly-Tyr-Gly-Ser-Ser-Ser-Arg-Arg(配列番号1) 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のジクロロメタン溶液を入れて、Fmoc-Arg(pbf)-OH 200mmole及びジイソプロピルエチルアミン(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DCMに溶かして10分間反応した後、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、Arg-(pbf)-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-Arg(pbf)-OH 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、全ての固体が溶解されるまで少なくとも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回攪拌して除去した。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、Arg(pbf)-Arg(pbf)-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、図1のように選定されたアミノ酸配列に基づき、Fmoc-Ser(tBu), Fmoc-Ser(tBu), Fmoc-Ser(tBu), Fmoc-Gly, Fmoc-Tyr(tBu), Fmoc-Gly, Fmoc-Ala, Fmoc-Ala, Fmoc-Lys(Boc), Fmoc-Asn(trt), Fmoc-Phe, Fmoc-Tyr(tBu), Fmoc-Phe, Fmoc-Glyの順に連鎖反応を行った。Fmoc-保護基を脱保護溶液で10分間ずつ2回反応した後、よく洗浄して除去した。製造されたペプチジルレジンを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た後、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%、EDT2.5%、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GFYFNKAAGYGSSSRRを1.18g合成した(収率69.6%%)。分子量測定器を利用して測定時、分子量1770.6(理論値1769.9)が得られた。
前記合成例1と同様な方法により合成するが、アミノ酸は、配列に符合するアミノ酸を使用して、配列番号2−5のペプチドを合成した。配列番号2(Gly-Tyr-Gly-Ser-Ser-Ser-Arg-Arg-Ala-Pro-Gln-Thr:GYGSSSRRAPQT)は、IGF−1のアミノ酸残基30−41、配列番号3(Glu-Ser-Ser-Phe-Arg-Ser-Ser-Asp-Leu-Arg-Arg-Leu:ESSFRSSDLRRL)は、IGF−1のアミノ酸残基46−57、配列番号4(Cys-Asp-Leu-Arg-Arg-Leu-Glu-Met-Tyr-Cys:CDLRRLEMYC)は、IGF−1のアミノ酸残基52−61、そして配列番号5(Arg-Arg-Leu-Glu-Met-Tyr-Cys-Ala-Pro-Leu-Lys-Pro:RRLEMYCAPLKP)は、IGF−1のアミノ酸残基55−66に該当する。
実施例2で製造された配列番号4をより安定にするために、C末端とN末端残基であるCysを利用して鎖化を試みた。製造した配列番号4のペプチドCys-Asp-Leu-Arg-Arg-Leu-Glu-Met-Tyr-Cys-OH 100gを1Lの10%DMSO/脱気蒸留水溶液に溶解した。pHを8.0に固定して8時間攪拌し、空気中で攪拌して空気酸化反応を誘導した。分取クロマトグラフィーを通じて鎖化されたCys-Asp-Leu-Arg-Arg-Leu-Glu-Met-Tyr-Cys-OH(1,10 Cyclized) 40mgを得た。最終的に合成された環状ペプチドの質量分析器による測定値は、1302.8であった。
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のジクロロメタン溶液を入れて、Fmoc-Cys(trt)-OH 200mmole及びジイソプロピルエチルアミン(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DCMに溶かして10分間反応した後、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、Cys-(trt)-CTLレジンを製造した。新しい反応器に10mlのDMF溶液を入れて、Fmoc-Tyr(tBu)-OH 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、全ての固体が溶解されるまで少なくとも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回攪拌して除去した。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、Tyr(tBu)-Cys(trt)-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、図1のように選定されたアミノ酸配列に基づき、M, E, L, R, R, L, D, C, Fmoc-b-Ala-OHの順に連鎖反応を行った。Fmoc-保護基を脱保護溶液で10分間ずつ2回反応した後、よく洗浄して除去した。100mmoleのFITCをDMFに溶かした後、200mmoleのDIEAと混ぜてレジンに入れ、1時間反応を維持した後、洗浄をした。製造されたペプチジルレジンを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下で真空に減圧し完全に乾燥した後、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%、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FITC-b-Ala-CDLRRLEMYCを0.78g合成した(収率52.6%)。C末端のCysと2番位置のCysを利用して鎖化を試みた。この時は、製造したFITC-b-Ala-CDLRRLEMYCペプチド100mgを取って、1Lの10%DMSO/脱気蒸留水溶液に溶解した。pHを8.0に固定して8時間攪拌し、空気中で攪拌して空気酸化反応を誘導した。分取クロマトグラフィーを通じて鎖化されたFITC-b-Ala-Cys-Asp-Leu-Arg-Arg-Leu-Glu-Met-Tyr-Cys-OH(2,11 Cyclized) 45mgを得た。
合成例1及び2に記載の5種のペプチドに対するインシュリン様成長因子−1の効能を分析するために、Rizzinoらの方法(Rizzino, et al. Cancer Res., 48:4266(1988))などを参照し、HaCaT角質細胞株とNIH3T3線維芽細胞を利用したSRB(Sulforhodamine B)の比色法を利用して測定した。
3T3線維芽細胞株を、250ml容量の組織培養用フラスコを利用して、100%FBS(fetal bovine serum)が含有されたEMEM(Eagle's minimal essential media, Gibco, U.S.A.)で培養した。48時間培養を完了した後、培養上清液を除去して、PBS(phosphate buffer saline)で1回洗浄した。合成例4で製造したFITC-b-Ala-CDLRRLEMYC(1-11 Cyclized)ペプチドを、PBSとDMSOに1mg/mlで溶かした後、前記培養された細胞に1時間処理した。培養液を除去した後、PBSで十分洗浄した後、蛍光及び光学顕微鏡で細胞の表面を観察した。
前記合成例から得られたアセチルデカペプチド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及び少量のオイルと共に混合した後、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、化粧品製造用として使用した。
前記剤形例1で製造されたナノソーム化ペプチドを含み、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。
前記剤形例1で製造されたナノソーム化ペプチドを含み、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。
前記剤形例1で製造されたナノソーム化ペプチドを含み、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。
前記合成例で製造されたペプチドを含み、下記組成からなる口腔清浄剤を、一般的な口腔清浄剤の製造方法により製造した。
前記合成例で製造されたペプチドを含み、下記組成からなる歯磨き剤を、一般的な歯磨き剤の製造方法により製造した。
合成したペプチドの化粧品としての有用性と生体内効能を調べるために、上記の剤形例3で製造した栄養クリーム及び同一組成のペプチドが入っていないクリームを利用して、マウス皮膚に適用させた。
Claims (7)
- ヒトインシュリン様成長因子(IGF-1)由来で、配列番号3のアミノ酸配列からなる、IGF−1活性を示すペプチド。
- 前記ペプチドのC−末端は、ヒドロキシ基(-OH)またはアミノ基(-NH2)に変形されたことを特徴とする、請求項1に記載のペプチド。
- 前記ペプチドのN−末端は、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。
- 配列番号3のアミノ酸配列からなるペプチドを有効成分として含む、皮膚状態の改善または歯周疾患の治療用組成物。
- 前記組成物は、(a)配列番号3のアミノ酸配列からなるペプチドの薬剤学的有効量、及び(b)薬剤学的に許容される担体を含む薬剤学的組成物であることを特徴とする、請求項4に記載の組成物。
- 前記組成物は、(a)配列番号3のアミノ酸配列からなるペプチドの化粧品学的有効量(Cosmetically effective amount)、及び(b)化粧品学的に許容される担体を含む化粧品組成物であることを特徴とする、請求項4に記載の組成物。
- 前記皮膚状態の改善は、シワの改善、皮膚弾力の改善、皮膚老化の防止、脱毛の防止または発毛の促進、皮膚保湿の改善、シミの除去、またはニキビの治療であることを特徴とする、請求項4に記載の組成物。
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US20020081324A1 (en) * | 2002-01-22 | 2002-06-27 | Twine Rebecca Wright | Method of treating aging skin and wrinkles using a combination of growth factors that is commercially prepared or derived from one's own blood |
KR20040076780A (ko) * | 2003-02-26 | 2004-09-03 | (주)케어젠 | 재조합 인슐린 유사 성장인자를 함유하는 화장료 조성물 |
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2007
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- 2007-03-06 JP JP2008558192A patent/JP4971373B2/ja active Active
- 2007-03-06 EP EP10171854.2A patent/EP2270039B1/en active Active
- 2007-03-06 US US12/224,788 patent/US20090169491A1/en not_active Abandoned
- 2007-03-06 EP EP07709097A patent/EP1989226A4/en not_active Withdrawn
- 2007-03-06 CN CN200780007937XA patent/CN101395179B/zh active Active
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Also Published As
Publication number | Publication date |
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KR100861914B1 (ko) | 2008-10-09 |
EP1989226A1 (en) | 2008-11-12 |
CN101395179B (zh) | 2013-01-02 |
CN101395179A (zh) | 2009-03-25 |
KR20070091568A (ko) | 2007-09-11 |
WO2007102686A1 (en) | 2007-09-13 |
US8263095B2 (en) | 2012-09-11 |
EP2270039B1 (en) | 2013-05-29 |
US20090169491A1 (en) | 2009-07-02 |
WO2007102686A8 (en) | 2010-03-04 |
EP1989226A4 (en) | 2009-11-18 |
US20100278756A1 (en) | 2010-11-04 |
EP2270039A1 (en) | 2011-01-05 |
JP2009529036A (ja) | 2009-08-13 |
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