JP5361988B2 - 成長因子−模倣(mimicking)ペプチド及びその用途 - Google Patents
成長因子−模倣(mimicking)ペプチド及びその用途 Download PDFInfo
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Description
(a)本発明の成長因子−模倣ペプチドは、天然のヒト成長因子と同様な機能または作用をすることができる。
(b)本発明のペプチドは、その安定性が、天然成長因子に比べ非常に優れており、また皮膚透過度が非常に高い。
(c)したがって、本発明のペプチドを含む組成物は、成長因子の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。
(d)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。
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-His(Trt)-OH(Bachem, スイス)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、His-(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-Thr(tBu)-OH(Bachem, スイス)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回に分けて入れて、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、Thr(tBu)-His(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。図1のように選定されたアミノ酸配列に基づき、Fmoc-Trp, Fmoc-Gly, Fmoc-Gly, Fmoc-Lys(Boc), Fmoc-Lys(Boc), Fmoc-Ser(tBu), Fmoc-Lys(Boc), 及びFmoc-Tyr(tBu)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。無水酢酸とDIEA、HoBtを入れて一時間アセチル化を行った後、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Ac-YKSKKGGWTHペプチド1を1.18g合成した(収率72.6%)。分子量測定器を利用して測定時、分子量1233.8(理論値1233.4)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2−4のペプチドを合成した。配列番号2(Tyr-Ile-Ser-Lys-Lys-His-Ala-Gly-Lys-Asn-Trp-Phe: YISKKHAGKNWF)は、aFGFF 111−122配列、配列番号3(Asp-Ser-His-Thr-Gln- Tyr-Cys-Phe-His-Gly-Thr: DSHTQYCFHGT)は、TGFα 10−20、配列番号4(Gly-Tyr-Val-Gly-Val-Arg-Cys-Glu-Ala-Ala-Asp-Leu-Asp-Ala: GYVGVRCEAADLDA)は、TGFαのアミノ酸残基38−49に該当する。合成されたペプチドに対する分子量測定器による測定値は、表1に示した通りである:
合成例1及び2に記載の4種のペプチドに対する成長因子−1の類似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。
48時間を培養したHaCaTに、合成したペプチド4種を処理して、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、Procollagen ELISAキット(Takara、Japan)及びFibronectinキット(CHEMICON、米国)を利用して行った。図5aから分かるように、本発明の4種のペプチドは、角質細胞のプロコラーゲン生成を増加させた。特に、ペプチド2が最も優れたプロコラーゲン生成促進能を示した。また、図5bから分かるように、本発明の4種ペプチドは、角質細胞のフィブロネクチン生成を増加させた。特に、ペプチド1及び4の優れたプロコラーゲン生成促進能を示した。
合成例1及び2を通じて製造された4種のペプチドとNIBSC(英国)で購入した標準品成長因子(KGF, aFGF及びTGF-α)を0.11mg/mlの濃度にPhosphate緩衝液で調製した。用意された溶液を1mlずつガラスバイアルに入れた後、37℃で静置した。37℃に静置された溶液を0, 5, 10, 20, 25, 30, 40, 60そして100日目にサンプリングして、日付別に遠心分離して変性されたペプチドや蛋白質を除去して、上澄液を取って、HPLCを利用して定量をした(図6)。合成ペプチドの場合、天然の成長因子より残存量が高くて、これを試料として試験例1と同一な方法で細胞に処理した後、MTT方法(Scudiero, D. A., et al. Cancer Res. 48:4827-4833(1988))を使用して、残存している活性を測定することによりペプチドの熱安定性を分析した結果、全ての場合、成長因子類より活性度がさらに高いことが分かった。
前記合成例から得られたペプチド4種を、50mgをそれぞれ正確に秤量した後、蒸留水500mlで十分に攪拌して溶解した。配合体溶液を、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、単独あるいは複合的に化粧品製造用に使用された。
前記実施例1で製造された4種のペプチドナノソームの中、少なくとも一種類のナノソームを含み、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4種のペプチドナノソームの中、少なくとも一種類のナノソームを含み、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4種のペプチドナノソームの中、少なくとも一種類のナノソームを含み、下記組成からなる栄養化粧水を、一般的な化粧水の製造方法により製造した。
前記実施例1で製造された4種のペプチドナノソームの中、少なくとも一種類のナノソームを含み、下記組成からなるエッセンスを、一般的なエッセンスの製造方法により製造した。
前記実施例1で製造された4種のペプチドナノソームを同時に含み、下記組成からなるハイドロゲルパッチを製造した(図7)。ドクターブレードとローラーで加工した後、焼成し、1×1cm2のハイドロゲル薄片を作って、実験に使用した。その薄片を図7に記載した。
Balb/Cマウスの背中部位の毛を除毛した後、手術用使い捨てナイフで約3mm〜5mmになるように傷を付けた。一日が経った後、製造された複合ペプチドハイドロゲルパッチと陽性対照群としてのaFGFをそれぞれの傷部位に塗布した。三日後、同量のペプチドを含むハイドロゲルパッチとaFGFを前の傷部位に再び付着した。7日後に傷治癒効果を肉眼で識別して確認し、その結果を図8に示した。図8から分かるように、何の処理もしなかった傷部位(陰性対照群)に比べて、複合ペプチド処理をした傷部位では傷治癒効果が肉眼で確認されて、特にペプチド接合体処理をした傷部位は、経過時間が長いほど、aFGF処理をした傷部位よりも著しく治療効果が高いことが肉眼で識別が可能であった。これは、本発明のペプチドが、天然の成長因子より体外でさらに安定して、長期間にかけて傷部位に作用をしたから出た結果と判断される。さらに、本発明のペプチドを含有した化粧品及びハイドロゲルの場合、成長因子の活性を維持しながら、増加された成体内半減期による皮膚改善効果及び創傷などの治療効果が明白であると判断される。
Claims (6)
- 成長因子由来であって、配列番号1乃至4に記載のアミノ酸配列から構成された群から選択される1種のアミノ酸配列からなる成長因子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。
- 請求項1乃至3のいずれかに記載のペプチドを有効成分として含む、皮膚状態の改善用組成物。
- 請求項1乃至3のいずれかに記載のペプチドを有効成分として含む、創傷治療用組成物。
- 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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