JP5255274B2 - 精製両親媒性ペプチド組成物およびその使用 - Google Patents
精製両親媒性ペプチド組成物およびその使用 Download PDFInfo
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- JP5255274B2 JP5255274B2 JP2007520521A JP2007520521A JP5255274B2 JP 5255274 B2 JP5255274 B2 JP 5255274B2 JP 2007520521 A JP2007520521 A JP 2007520521A JP 2007520521 A JP2007520521 A JP 2007520521A JP 5255274 B2 JP5255274 B2 JP 5255274B2
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Description
本発明は高純度の両親媒性ペプチド組成物に関する。
一般的に、身体は傷害を受けた組織を再生してもとの組織と同様の特性を有する新しい組織を形成することができる。例えば小型の切り傷は永久的な瘢痕を形成することなく治癒し、そして、骨の簡潔な骨折は骨の2つの切片を結合する新しい骨の形成により治癒する。しかしながら結合組織の細胞及び他の臓器の細胞は足場依存性であり、それらは正常な生理学的挙動を示すためにはスカホールドを必要とする。組織の損傷が広範であるか、又は大型の間隙が存在する場合は、創傷内に遊走した細胞は適切な足場を発見できず、創傷の両端の健常な組織の間の間隙を架橋する瘢痕組織を形成する。瘢痕組織は元の組織と同じ機械的及び生物学的特性を有していない。例えば皮膚の瘢痕組織は元の組織ほど柔軟性を有していない。骨の瘢痕組織は未傷害の骨ほど強度がなく、骨が再度破断しやすい弱点箇所を与える場合が多い。関節の軟骨のような一部の組織は自然に再生せず、そして治癒は瘢痕組織の形成により進行するのみである。
「スカホールド」とは、細胞を支持することができる三次元構造を意味する。細胞はスカホールドによりカプセル化されるか、又はスカホールドの表面上の層内に配置させてよい。スカホールドのβ−シート二次構造は標準的な円偏光二色性を用いて、約218nmにおける最小吸光度及び約195nmにおける最大吸光度を検出することを確認し得る。スカホールドはペプチドの自己組立により形成され、L−アミノ酸、D−アミノ酸、天然アミノ酸、非天然アミノ酸又はこれらの組み合わせを包含し得る。L−アミノ酸がスカホールド内に存在する場合は、スカホールドの分解により宿主組織により再利用されるアミノ酸が生じる。ペプチドは化学誘引物質又は治療活性化合物のような化合物に共有結合され得る。ペプチドは天然又は組み換えの原料から化学合成又は精製してよく、ペプチドのアミノ末端及びカルボキシ末端は保護されていても保護されていなくてもよい。ペプチドスカホールドは相互に相補であり構造的に適合性のあるペプチドの異なる分子種1つ以上から形成されてよい。隣接するペプチド由来の2つの同様に荷電した残基の反発性の対形成のようなミスマッチペアを含有するペプチドもまた、ペプチド間の安定化相互作用が破壊的な力より優位となる場合はスカホールドを形成する。スカホールドは本明細書においてはペプチド構造、ペプチドヒドロゲル構造、ペプチドゲル構造又はヒドロゲル構造とも称する。
1つの局面において、本発明は相補的であり構造的に適合し、そして自己組立によりβ−シート巨視的スカホールドとなる、交互する親水性アミノ酸及び疎水性アミノ酸を有する両親媒性のペプチド鎖を含む組成物である。ペプチド鎖は少なくとも8アミノ酸を含有し、そしてペプチド鎖の少なくとも約75%、少なくとも約80%、少なくとも約85%、少なくとも約90%、少なくとも約95%又は少なくとも約99%が同じ配列を有する。
本明細書に記載した本発明の組成物は12〜16アミノ酸を有する精製された両親媒性ペプチドを包含する。ペプチドは少なくとも75%の純度である。1つの実施形態において、ペプチドは保護基に連結する側鎖内の基を含むアミノ酸を準備すること、アミノ酸を組み立てて両親媒性のペプチド鎖とすること、及び、トリフルオロ酢酸又はその塩の何れかの非存在下にアセテート塩にペプチドを反応させることにより保護基を除去することにより調製してよい。
本発明の使用に適切であるペプチド配列は、参照により本明細書に組み込まれる、米国特許第5,670,483号及び同第5,955,343号及び米国特許出願第09/778,220号に報告されているものを包含する。これらのペプチド鎖は、1価のカチオンのような電解質の存在下で自己組立して非常に安定なβ−シートの巨視的構造を形成することができる、交互する親水性アミノ酸及び疎水性アミノ酸からなる。ペプチド鎖は相補的であり、構造的に適合している。構造内のペプチド鎖の側鎖は、2つの面、即ち、荷電したイオン性側鎖を有する極性の面及びアラニン又は他の疎水性の基を有する非極性の面に分割される。これらのイオン性の側鎖は、正荷電のアミノ酸残基及び負荷電のアミノ酸残基が相補性のイオン対を形成できるという点において、相互に自己相補的である。従ってこれらのペプチド鎖はイオン性自己相補性ペプチド、又はI型自己組立ペプチドと称する。イオン性残基が1つの正荷電残基と1つの負荷電残基とで交互である場合(−+−+−+−+)、このペプチド鎖は「モジュラスI」と記載され;イオン性残基が2つの正荷電残基と2つの負荷電残基とで交互である場合(−−++−−++)は、このペプチド鎖は「モジュラスII」と記載される。本発明で使用するための例示されるペプチド配列は、表1に列挙するものを包含する。一部の実施形態においては、本発明で使用するペプチド配列は少なくとも12又は18アミノ酸残基を有する。D型及びL型の両方のアミノ酸をペプチド鎖の作製に使用してよい。それらは同じ鎖内で混合されていてよく、或いは、自身がD型及びL型のアミノ酸のみを含んでいる個々の鎖の混合物を有するペプチド組成物を調製してよい。
本発明で使用するためのペプチド鎖は、溶液相合成および固相合成を包含する、当該分野でよく知られた手法を用いて作製してよい。これらの手法は、驚くべき特性(貯蔵寿命、分解速度、溶解度及び機械的特性が挙げられるが、これらに限定されない)を最終組成物に与える純度レベルにおいて、本明細書に記載したペプチド鎖を作製するために最適化されてもよい。
形成されるまで反復する。当業者の知る通り、4量体同士の幾つかの組み合わせは16量体の迅速な形成をもたらす。
精製された生成物は粉末状態で保存するか、又は水溶液中に再溶解してよい。ペプチド産物は以前の製剤よりも水溶性が有意に高値であり、そして2%又は3%超の濃度が達成される。例えば超音波又は振とうテーブルによる攪拌を行えばペプチド鎖が溶液となり易い。溶液中のペプチドの濃度は所望の用途に応じて変動してよい。1つの実施形態において、水中のペプチド鎖の濃度は約0.25%〜約7%、例えば約0.5%、約1%、約2%、約3%、約4%、約5%又は約6%であってよい(全濃度は特段の記載が無い限り、重量%である)。別の実施形態においては、ペプチド鎖の濃度はむしろより高値となり、例えば約7%〜約10%、例えば約8%又は約9%であってよい。
ペプチド溶液を1価の塩の溶液に曝露することにより安定なスカホールドを形成してよい。十分な電解質を溶液に添加することにより、ペプチドからβ−シート巨視的構造への自己組立が開始される。本発明の特定の実施形態においては、添加される電解質の濃度は少なくとも5、10、20又は50mMである。より低濃度、例えば0.1〜1mm又はより高濃度も使用してよい。濃度の選択は部分的にはペプチドゲルの所望のイオン強度に依存しており、そしてゲル化の速度にも影響する。適当な電解質は例えばLi+、Na+、K+及びCs+を包含するがこれらに限定されない。電解質はペプチド鎖を自己組立させて機械的攪拌に対して安定なスカホールドとする。
1.酢酸アンモニウム(実験室調製)
2.クエン酸ナトリウム(実験室調製)
3.酢酸ナトリウム(実験室調製)
4.炭酸水素ナトリウム(Abbott,Inc.作製の臨床用等級)
5.HEPES(Stem Cell Technologies,Inc.作製の研究用等級)
6.Tris−HCl(実験室調製)
7.トロメタミン、別名THAM(Abbott,Inc.作製の臨床用等級)
8.Ca及びMg非含有のリン酸塩緩衝食塩水(Gibc−BRL)。
本明細書に記載したペプチドゲルは、それに細胞が結合し、その上で創傷部位の内部に遊走するマトリックスを提供する。本明細書に開示したペプチドスカホールドは固体マトリックスというよりはむしろ介入する空間を有するナノ繊維のネットワークを含む。そのような構造は、他の培養手法及び材料により可能となるものよりも身体内の細胞の環境により近似した態様において、細胞の浸潤及び細胞−細胞の相互作用を可能にする。端部から単に治癒する代わりに、細胞がスカホールドの中心にまで遊走するに従って創傷の全領域が同時に再生されるのである。
Claims (3)
- 以下の工程:
保護基に連結する側鎖内の基を含むアミノ酸を準備する工程;
該アミノ酸を組み立てて複数の両親媒性のペプチド鎖とする工程であって、該複数の両親媒性ペプチド鎖における該ペプチド鎖の各々はRADARADARADARADAを含むアミノ酸配列またはそのフラグメントを含む、工程;
該ペプチド鎖を酸と反応させることにより該保護基を除去する工程;および、
該酸を非フッ素化アセテート塩と交換する工程;
を含む、75%〜99%がRADARADARADARADAを含む同一のアミノ酸配列を有する複数のペプチド鎖の調製方法。 - 前記非フッ素化アセテート塩が酢酸ナトリウム及び酢酸カリウムから選択される、請求項1に記載の方法。
- 前記酸がトリフルオロ酢酸である、請求項1に記載の方法。
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- 2005-07-06 EP EP21215151.8A patent/EP4023240A1/en active Pending
- 2005-07-06 WO PCT/US2005/024198 patent/WO2006014570A2/en active Application Filing
- 2005-07-06 EP EP05770153A patent/EP1843776A4/en active Pending
- 2005-07-06 EP EP15195734.7A patent/EP3031466B1/en not_active Revoked
- 2005-07-06 US US11/176,781 patent/US20060084607A1/en not_active Abandoned
-
2012
- 2012-08-27 JP JP2012186897A patent/JP5730828B2/ja active Active
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2013
- 2013-04-19 US US13/866,135 patent/US20130281547A1/en not_active Abandoned
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2016
- 2016-03-09 US US15/065,758 patent/US20160317607A1/en not_active Abandoned
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- 2023-02-13 US US18/109,096 patent/US20230190864A1/en active Pending
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
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US10576123B2 (en) | 2008-10-06 | 2020-03-03 | 3-D Matrix, Ltd. | Tissue occluding agent comprising an IEIKIEIKIEIKI peptide |
US10596225B2 (en) | 2008-10-06 | 2020-03-24 | 3-D Matrix, Ltd. | Tissue occluding agent comprising an IEIKIEIKIEIKI peptide |
US11801281B2 (en) | 2008-10-06 | 2023-10-31 | 3-D Matrix, Ltd. | Tissue occluding agent comprising an ieikieikieiki peptide |
US10793307B2 (en) | 2012-07-06 | 2020-10-06 | 3-D Matrix, Ltd. | Fill-finish process for peptide solutions |
US12006085B2 (en) | 2012-07-06 | 2024-06-11 | 3-D Matrix, Ltd. | Fill-finish process for peptide solutions |
US10654893B2 (en) | 2014-03-10 | 2020-05-19 | 3-D Matrix, Ltd. | Self-assembling peptide compositions |
US11090398B2 (en) | 2014-03-10 | 2021-08-17 | 3-D Matrix, Ltd. | Sterilization and filtration of peptide compositions |
US10814038B2 (en) | 2016-01-06 | 2020-10-27 | 3-D Matrix, Ltd. | Combination compositions |
US11324703B2 (en) | 2017-12-15 | 2022-05-10 | 3-D Matrix, Ltd. | Surfactant peptide nanostructures and uses thereof in drug delivery |
Also Published As
Publication number | Publication date |
---|---|
WO2006014570A3 (en) | 2006-04-06 |
EP1843776A4 (en) | 2011-05-11 |
EP3031466A1 (en) | 2016-06-15 |
US20130281547A1 (en) | 2013-10-24 |
CA2572964A1 (en) | 2006-02-09 |
JP2012250988A (ja) | 2012-12-20 |
US20060084607A1 (en) | 2006-04-20 |
WO2006014570A2 (en) | 2006-02-09 |
JP5730828B2 (ja) | 2015-06-10 |
EP3031466B1 (en) | 2018-11-28 |
CA2572964C (en) | 2018-03-06 |
US20160317607A1 (en) | 2016-11-03 |
EP4023240A1 (en) | 2022-07-06 |
US20230190864A1 (en) | 2023-06-22 |
EP4049671A1 (en) | 2022-08-31 |
EP1843776A2 (en) | 2007-10-17 |
JP2008505919A (ja) | 2008-02-28 |
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