JP5535620B2 - 細胞外マトリックスタンパク質の合成を誘導するペプチドフラグメント - Google Patents
細胞外マトリックスタンパク質の合成を誘導するペプチドフラグメント Download PDFInfo
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- JP5535620B2 JP5535620B2 JP2009515450A JP2009515450A JP5535620B2 JP 5535620 B2 JP5535620 B2 JP 5535620B2 JP 2009515450 A JP2009515450 A JP 2009515450A JP 2009515450 A JP2009515450 A JP 2009515450A JP 5535620 B2 JP5535620 B2 JP 5535620B2
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Description
アミノ酸配列モチーフが、GxxG又はPxxPであることを特徴とするテトラペプチドを開示している。ここで、G(グリシン)とP(プロリン)は一定で、xは可変アミノ酸である。このテトラペプチドは、ECMタンパク質、IV型コラーゲンの主要な配列中に何度も出現する配列に由来する。開示された配列は、SEDERMA SAS(フランス)から商標MATRIXYL(TM)として販売されているKTTKSを含む以前から公知のペプチド配列以上に、全タイプのコラーゲンの生成を誘導する。さらに、種々の複数反復配列の組み合わせを含む組成物がさらなるコラーゲン合成反応を引き起こす。種々のECMタンパク質中に存在するペプチドの組み合わせは、更なる利点が期待される。
本発明の一つの実施形態は、モチーフGxxG又はモチーフPxxPを含む単離されたテトラペプチドに関する。本実施形態において、G(グリシン)とP(プロリン)は一定で、xは可変アミノ酸である。ペプチドは、一般的に上記記載のペプチドとすることができ、より好ましくはSEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、又はSEQ ID NO:16とすることができる。
本発明の更なる実施形態には、上記ペプチドの使用方法に関する。使用方法には、シングルペプチドの使用や、2つあるいはそれ以上のペプチドの組み合わせた使用も含むことができる。
1984 (Ragnarsson U., ed.) Almoqvist and Wiksell Int., Stockholm (Sweden), pp.185-188, であり、これらは、引用をもって全文の記載加入とする。望ましくは、伸長中のペプチド鎖にアミノ酸を逐次付加できる機械によってペプチドは生成されるであろう。しかしながら、標準溶液による位相法を用いて作製してもよい。
コラーゲンIVのテトラペプチドの反復配列のうち、図1中、比較的高比率なものは、モチーフGxxGである(xは任意のアミノ酸である)。これらの多くは、図1中、SEQ ID NO:45として示された完全なコラーゲンIV全配列の一部としてインサイチュで示されている。コラーゲンIVは他の特定のECM要素と相互作用する役割があるので最初に調べた(Gregory Schultz et al.,2005を参照)。コラーゲンIV中にモチーフGxxGを有する配列があり、それらは10回以上も現れた(GxxG中、xxはvp、ek、fp、lp、pp、sp、ep、ip、pk、qp及びtpで表されている)。これらのテトラペプチド配列のうち、11配列中8配列は、位置3にプロリンを含んでおり、11配列中2配列では、位置2にプロリンを含み、11配列中1配列は、位置2と位置3にプロリンを含み、11配列中1配列には、プロリンを含んでいない。開示した配列はREPLIKINES(TM)と称されている。“REPLIKINES”は、ECMタンパク質中に何回も出現する(すなわち反復された)短い配列として定義される。この配列は、1のECMタンパク質中に存在するかもしれない(例えばコラーゲンIV)。配列は、複数のECMタンパク質(例えば全てのコラーゲン、エラスチン、ラミニンなど)に存在することが望ましい。複数のECMタンパク質に、この配列が存在することで、フラグメントが、ECM合成や修復を促進できる可能性が増大する。
モチーフGxxGを有するコラーゲンIVのテトラペプチドの反復配列が比較的高比率のことに加えて、GxxxGやPxxPのテトラペプチド配列から1アミノ酸フレームシフトを起こした他のテトラペプチド配列は、同定されている。これら配列は、ECMタンパク質中で反復し、又は1度だけ現れている可能性があり、ここで述べたようにGxxG又はPxxPのテトラペプチド配列のいずれかから1アミノ酸位置ずれたところにある可能性がある。これらテトラペプチド配列は、フレームシフト活性と称される。このようなフレームシフト活性は、従って、フレームシフトの方向によって、2番目又は3番目の位置にGかPのいずれかをが含んでいる可能性がある。さらに、フレームシフト活性は、本出願に開示された他のテトラペプチドと結合し、コンビカイン(combikine)を形成する可能性があることが認識されている。このようなコンビカインの例は、H06とH15である。
実施例1と2で同定されたいくつかの配列は、標準的なペプチド化学を用いて合成され、皮膚繊維芽細胞からコラーゲンの刺激のために分析された。合成されたペプチドはC末端でアミノ化され、遊離酸の形態と比べて、テトラペプチドのプロテアーゼ分解に対する感受性を低くしたり溶解性を高めている。ヒト表皮繊維芽細胞は、96ウェルプレートで、37℃、CO2濃度5%、24時間及び48時間低濃度の血清成長因子(Cascade Biologics, Portlamd, OR; Cat. No. S-003-10)を加えてさらに最終ペプチド濃度50μg/mLとなるようサンプルペプチドを含ませた完全細胞培養培地(Cascade Biologics, Portlamd, OR; Cat. No. M-106-500)150μL中でインキュベートした。各ウェルに10,000で種付けした。インキュベートの後、100μLの培地サンプルを各ウェルから取り出し、コラーゲン合成を分析した。
活性テトラペプチドの不均一集団はテトラペプチドの均一試料よりも高レベルでコラーゲン生成を刺激する可能性がある。不均一組成物の成分は、コンビキン(COMBIKINES(TM))と呼ばれている。コンビキンは、一又はそれ以上のターゲット細胞タイプに、より強く広範囲に影響を与えるために生成するよう結合したREPLILINESのグループである。ペプチドH11(SEQ ID NO:5)、H12(SEQ ID NO:6)、H13(SEQ ID NO:7)、H14(SEQ ID NO:8)は、最終濃度50μg/mLに結合され、個々のペプチドと同じプロトールを用いて分析した。予想通り、24時間時点での結果は、個々の誘導物の平均値と等しかった。しかしながら、48時間でのペプチドの組合せは、43μg/mLのレベルまでコラーゲンを誘導した。驚くべきことにこの量は、4つの個々のペプチドの予想平均値(21μg/mL)をはるかに上回っていた(表5を参照)。このように、ペプチドの特定の組み合わせは、同一濃度における個々のペプチドよりもかなりの程度でコラーゲン生成を刺激する可能性がある。さらにコラーゲン、ラミニン、エラスチンのような様々なECM源からのテトラペプチドは、様々なECMタンパク質の誘導を高める可能性がある(表1、表5を参照)。
高コストなペプチド合成が、生物活性のあるペプチドの不均一組成物を作製する実現可能性を制約している。本発明は、この制約を大いに軽減するものである。なぜなら、ここで開示している配列は共通性を有し(例えばグリシン又はプロリンが両端にある)、範囲が位置2と位置3で異なるテトラペプチドは、一つの製造ラインで合成できるからである。合成ペプチドは、当業者の既知のいかなる方法でも作製することができる(Benoiton, N., Chemistry of Peptide Synthesis, CRC (2005))。ペプチド製造中、アミノ酸混合物が均一サンプルに代えて添加される。得られるペプチドを所望の割合で獲得するために、混合位置に加えられるアミノ酸濃度の正確な比率を決定するための化学反応は前述されている(Greenbaum et al., Molecular and Cellular Proteomics 1:60-68, 2002; Krstenansky et al., Letters in Drug Design and Discovery 1:6-13, 2004;これらの文献は、引用をもって全文の記載加入とする)。この方法論を用いて、不均一ペプチドのライブラリーは、一のペプチドを合成する費用とほぼ同様に作製することができる。
コラーゲンは、損傷治癒の全ての段階において鍵となる成分である。コラーゲン生成の促進は、コラーゲンネットワークにダメージが生ずること(例えば酵素や物理的な破壊)に影響する。実際、事実上のコラーゲンネットワークの総合的な崩壊により治癒が引き起こされる。したがって、コラーゲン刺激剤は、あるマトリックスの再構築を調整し、損傷治癒を高める複合エフェクター分子としても働く可能性がある。
Claims (12)
- SEQ ID NO:5(GEPG)、SEQ ID NO:8(GEKG)、又は、SEQ ID NO:3(GSPG)であって、ヒトの皮膚におけるコラーゲンの生成を刺激するテトラペプチド。
- テトラペプチドは、遊離酸であるか、カルボキシ末端でアミド化されている請求項1に記載のテトラペプチド。
- 請求項1又は請求項2に記載のテトラペプチドと、薬学的に認められたキャリアを含んでいる組成物。
- テトラペプチドは、有効濃度0.01μg/mLから100μg/mLの範囲で存在する請求項3に記載の組成物。
- テトラペプチドは、有効濃度0.1μg/mLから1μg/mLの範囲で存在する請求項3に記載の組成物。
- 組成物は、エアロゾル、エマルション、液体、ローション、クリーム、ペースト、軟膏、又は、発泡体の形態である請求項3乃至5の何れかに記載の組成物。
- SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7及びSEQ ID NO:8のテトラペプチドの混合物を含んでいる組成物。
- スキンケアに用いられる請求項3乃至7の何れかに記載の組成物。
- ダメージを受けた皮膚を治す又は健康的な皮膚を維持する製剤に用いられる請求項1又は2に記載のテトラペプチド。
- SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7及びSEQ ID NO:8のテトラペプチドの混合物を含んでおり、ダメージを受けた皮膚を治す又は健康的な皮膚を維持する製剤に用いられる組成物。
- 創傷の治療に使用される、請求項3乃至8及び請求項10の何れかに記載の組成物。
- 創傷は、老化、病気、けが、外傷、又は、手術によって生じたものである、請求項11に記載の組成物。
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WO2009111471A2 (en) * | 2008-03-03 | 2009-09-11 | Henry Ford Health System | Collagen-derived peptide as biomarker, therapeutic agent and target |
WO2010075849A1 (de) * | 2008-12-30 | 2010-07-08 | Gkl-Biotec Ag | Peptidkombination |
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EP3515928A4 (en) | 2016-09-23 | 2020-04-01 | Duke University | UNSTRUCTURED NON-REPITITIVE POLYPEPTIDES WITH LCST BEHAVIOR |
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