JP2011078806A - 合成ヘパリン結合成長因子類似体 - Google Patents
合成ヘパリン結合成長因子類似体 Download PDFInfo
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- JP2011078806A JP2011078806A JP2010262096A JP2010262096A JP2011078806A JP 2011078806 A JP2011078806 A JP 2011078806A JP 2010262096 A JP2010262096 A JP 2010262096A JP 2010262096 A JP2010262096 A JP 2010262096A JP 2011078806 A JP2011078806 A JP 2011078806A
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Abstract
【解決手段】ペプチド鎖または複数の鎖が、ヘパリン結合成長因子レセプターを結合し、そして特に、疎水性リンカーでありうるリンカーによって、ヘパリン結合ドメインを含む非シグナル発生ペプチドに共有結合で結合されるものである、少なくとも1個のペプチド鎖、好ましくは2つの三官能アミノ酸残基から構成されるジペプチド分岐部位から分岐した2個のペプチド鎖を有する合成ヘパリン結合成長因子類似体及び合成ヘパリン結合成長因子類似体を表面被覆剤とした医療用デバイス。
【選択図】なし
Description
本出願は、2002年8月20日に提出された「合成ヘパリン結合成長因子類似体」と題される米国特許出願番号第10/224,268号の一部継続出願であり、そしてそれに対して優先権を主張し、そしてその明細書は、ここに参照して組み込まれる。
本発明は、米国エネルギー省により授与される契約番号DE−AC02−98CH10886号の下に米国連邦政府支援を伴い発明された。米国連邦政府が本発明のあらゆる権利を有する。
各Xは、(i)最小3個のアミノ酸残基を有し、(ii)最大約50個のアミノ酸残基を有し、そして(iii)ヘパリン結合成長因子レセプター(HBGFR)を結合するペプチド鎖である;R1は、アミノ酸残基であり、Xは、R1のN末端を通して、またはR1の側鎖を通して共有結合で結合されている;R2は、三官能性アルファアミノ酸残基であり、Xは、R2の側鎖を通して共有結合で結合されている;Yは、n=0の場合、R1およびZに、またはn=1の場合、R2およびZに共有結合で結合された0個から約50個の原子までの鎖を包含するリンカーである;Zは、ヘパリン結合ドメインを包含する非シグナル発生ペプチド鎖であり、そして(i)最小1個のヘパリン結合モチーフ、(ii)最大約10個のヘパリン結合モチーフ、および(iii)最大約30個のアミノ酸を包含するアミノ酸配列を包含する;そしてnは、0または1であり、n=1の場合、ペプチド鎖Xは同一である。
R3およびR5は、独立に、NH2;N末端NH2、NH3 +、またはNH基あるいは対応のアシル化誘導体を含む、線状または分岐C1からC17までのアルキル、アリール、ヘテロアリール、アルケン、アルケニルまたはアラルキル鎖を有するアシル基であるか、またはN末端NH2、NH3 +、NH基あるいは対応のアシル化誘導体を有するアミノ酸、ジペプチドまたはトリペプチドである;R4は、−OH、NH2、NH−R6であるか、またはC末端−OH、NH2、またはNH−R6を有するアミノ酸、ジペプチドまたはトリペプチドである;R6は、脂肪族C1からC17までの鎖である;各Xは、(i)最小3個のアミノ酸残基を有し、(ii)最大約50個のアミノ酸残基を有し、そして(iii)HBGFRを結合するペプチド鎖である;J1およびJ2は、各々独立に、各Xが、J1およびJ2の側鎖を通して共有結合で結合される三官能性アルファアミノ酸残基である;Yは、n=0である場合、J1およびZに、あるいはn=1である場合、J2およびZに共有結合で結合された0から約50個までの原子の鎖を包含するリンカーである;Zは、ヘパリン結合ドメインを包含する非シグナル発生ペプチドであり、そして(i)最小1個のヘパリン結合モチーフ、(ii)最大約10個のヘパリン結合モチーフ、および(iii)最大約30個のアミノ酸を包含するアミノ酸配列を包含する;そしてnは、0または1であり、n=1の場合、合成ペプチド鎖Xは同一である。
式IからIVまでのヘパリン結合成長因子
式IからIVまでの合成HBGF類似体の領域XおよびZは、アミノ酸残基を含み、そして都合により領域Yは、アミノ酸残基を含む。アミノ酸残基は、Rが水素またはあらゆる有機基でありうる−NHRCO−として定義される。アミノ酸は、D−アミノ酸またはL−アミノ酸でありうる。さらに、アミノ酸は、アミノ酸の炭素鎖の長さによって、α−アミノ酸、β−アミノ酸、γ−アミノ酸、またはδ−アミノ酸などでありうる。
FGF合成類似体
別の特定の態様では、本発明は、合成FGFペプチド類似体を提供する。Xが、FGF類似体である、式IからIVまでのいずれかによって表される合成FGF類似体は、23のFGF−1からFGF−23まですべてを含めた既知FGFのいずれかのようなすべてのFGFでありうるFGFの類似体である。
別の特定の態様では、本発明は、合成VEGFペプチド類似体を提供する。示される合成VEGF類似体は、1つの実施態様では、X領域のアミノ酸配列がAPMAEGGGQNHHEVVKFMDV(配列番号:12)であるVEGF類似体を含む。別の実施態様では、X領域のアミノ酸配列がGATWLPPNPTK(配列番号:13)である合成VEGFペプチド類似体を提供する。さらに別の実施態様では、X領域のアミノ酸配列がNFLLSWVHWSLALLLYLHHA(配列番号:14)である合成VEGFペプチド類似体を提供する。
別の特定の態様では、本発明は、合成BMPペプチド類似体を提供する。合成骨形成タンパク質類似体は、X領域がアミノ酸配列LYVDFSDVGWNDW(配列番号:15)、AISMLYLDENEKVVL(配列番号:16)、ISMLYLDENEKVVLKNY(配列番号:17)、EKVVLKNYQDMVVEG(配列番号:18)、LVVKENEDLYLMSIAC(配列番号:19)、AFYCHGECPFPLADHL(配列番号:20)、またはPFPLADHLNSTNHAIVQTLVNSV(配列番号:21)である実施態様を含む。
本発明の類似体の合成は、当業界で周知である多様な化学的方法のいずれかにより達成されうる。このような方法は、ベンチスケールの固相合成および市販で入手可能な多くのペプチド合成機のいずれか1つでの自動ペプチド合成を含む。好ましくは、合成機は、99パーセントより大きな周期当たりのカップリング効率を示す。
本発明のHBGF類似体は、例えば、種々の疾患の予防または治療のための溶解性薬剤としての投与のように、溶解性予防薬または治療用医薬製剤としてを含めて、例えば癌療法および放射線防御での使用を含めて、多くの点で有用である生物学的に活性な分子の費用効率の高い、そして潜在的に制限のない源を提供する。
繊維芽細胞成長因子FGFは、間葉、上皮、および神経外胚葉の細胞型の正常な成長および分化を制御する関連タンパク質のファミリーを構築する。相同体は、広範で多様な種で見られた。FGFは、ヘパリンに非常に高い親和性を示し、したがって、ヘパリン結合成長因子(HBGF)とも称される。ここで使用される場合、用語「HBGF」は、全てのFGFを含む。
Claims (7)
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R 3 およびR 5 は、各々独立に、NH 2 ;N末端NH 2 、NH 3 + 、NH基あるいは対応するアシル化誘導体を含む、直鎖または分岐C 1 からC 17 までのアルキル、アリール、ヘテロアリール、アルケン、アルケニルまたはアラルキル鎖を有するアシル基であるか、またはN末端NH 2 、NH 3 + 、NH基あるいは対応するアシル化誘導体を有するアミノ酸、ジペプチドまたはトリペプチドである;
R 4 は、−OH、NH 2 、NH−R 6 であるか、またはC末端−OH、NH 2 、またはNH−R 6 を有するアミノ酸、ジペプチドまたはトリペプチドである;
R 6 は、脂肪族C 1 からC 17 までの鎖である;
各Xは、配列番号6〜22から選択され;
J 1 およびJ 2 は、各々独立に、三官能性アルファアミノ酸残基であり、各Xは、J 1 およびJ 2 の側鎖を通して共有結合で結合される;
Yは、3個のアミノヘキサン酸残基の鎖からなるリンカーある;
Zは、配列番号2、ヘパリン結合ドメインからなる非シグナルペプチド、
nは、0または1であり、n=1の場合、合成ペプチド鎖Xは同一である、
式IIで表されるヘパリン結合成長因子(HBGF)類似体を、その表面に、非共有結合を介して、被覆した医療用デバイスを供し、そして哺乳類の表面上に医療用デバイスを乗せるか、またはその中に医療用デバイスを移植することを包含する、活性ヘパリン結合成長因子類似体を哺乳類に送出するデバイス。 - 医療用デバイスは、縫合糸、移植片材料、外傷被覆材、神経ガイド、骨ワックス、動脈瘤コイル、塞栓形成粒子、微細ビーズ、ステント、歯科移植片、または骨プロテーゼ、組織足場、または徐放性薬剤送出デバイスである請求項1に記載のデバイス。
- 非共有結合は、合成ヘパリン結合成長因子類似体のヘパリン結合ドメインと、医療用デバイスの表面に結合したヘパリン含有化合物の間の結合である請求項1に記載のデバイス。
- ヘパリン含有化合物は、ベンジル−ビス(ジメチルシリルメチル)オキシカルバモイル−ヘパリンである請求項3に記載のデバイス。
- 医療用デバイスの表面は、ステンレス鋼、チタン、プラチナ、タングステン、セラミックス、ポリウレタン、ポリテトラフルオロエチレン、伸縮ポリテトラフルオロエチレン、ポリカーボネート、ポリエステル、ポリプロピレン、ポリエチレン、ポリスチレン、ポリ塩化ビニル、ポリアミド、ポリアクリレート、ポリウレタン、ポリビニルアルコール、ポリカプロラクトン、ポリラクチド、ポリグリコライド、ポリシロキサン、天然ゴム、人工ゴム、ブロック重合体またはブロック重合体の共重合体である請求項1に記載のデバイス。
- ポリシロキサンが、2,4,6,8−テトラメチルシクロテトラシロキサンである請求項5に記載のデバイス。
- X及びZは合成ペプチド鎖である請求項1に記載の合成ヘパリン結合成長因子類似体。
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