JP2016041711A - ペプチド骨格およびc末端改変を持つ改変したコンプスタチン - Google Patents
ペプチド骨格およびc末端改変を持つ改変したコンプスタチン Download PDFInfo
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- JP2016041711A JP2016041711A JP2015198674A JP2015198674A JP2016041711A JP 2016041711 A JP2016041711 A JP 2016041711A JP 2015198674 A JP2015198674 A JP 2015198674A JP 2015198674 A JP2015198674 A JP 2015198674A JP 2016041711 A JP2016041711 A JP 2016041711A
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- Prior art keywords
- peptide
- trp
- compstatin
- ile
- compstatin analog
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Landscapes
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Abstract
【解決手段】Xaa1−Cys−Val−Xaa2−Gln−Asp−Xaa3−Gly−Xaa4−His−Arg−Cys−Xaa5(環状C2−C12)の配列を有するペプチドを含むコンプスタチンアナログ。コンプスタチンアナログおよび医薬上許容される担体を含む医薬組成物。補体活性化の抑制のための医薬製造におけるコンプスタチンアナログの使用。
【選択図】なし
Description
米国特許法第202(c)より、米国政府が、助成番号GM62134下で国立衛生研究所からの基金で部分的になされた、本明細書に記載された発明にある権利をし得ると認められる。
Xaa1−Cys−Val−Xaa2−Gln−Asp−Xaa3−Gly−Xaa4−His−Arg−Cys−Xaa5(環状C2−C12)であり、
[式中、8位のGlyを改変して、その位置でのペプチドの骨格立体構造を拘束し、
Xaa1は、Ile、Val、Leu、Ac−Ile、Ac−Val、Ac−Leu、またはGly−Ileを含むジペプチドであり;
Xaa2はTrpまたはTrpのアナログであり、ここに、Trpのアナログは、Trpと比較して疎水性特性を増加させ;
Xaa3は、Trp、またはインドール環の水素結合ポテンシャルを増加させる、そのインドール環に対する化学的修飾を含むTrpのアナログであり;
Xaa4は、His、Ala、PheまたはTrpであり;および
Xaa5は、Thr、Ile、Leu、Nle、N−メチルThrまたはN−メチルIleのいずれかのカルボキシ末端の−OHが、−NH2により所望により置換されていてもよいThr、Ile、Leu、Nle、N−メチルThrまたはN−メチルIleである]である。
アルブミン結合ペプチドは、配列RLIEDICLPRWGCLWEDD(配列番号:14)を含み得る。特定の具体例は、アルブミン結合ペプチドに結合した配列番号:5、7、8、9、10または11のいずれか1つを含む。所望により、化合物およびアルブミン結合ペプチドをスペーサーにより分離する。スペーサーは、ミニ−PEGまたはミニ−PEG3のごときポリエチレングリコール(PEG)分子であり得る。
定義:
本発明の方法および他の態様に関する種々の用語は、本明細書および特許請求の範囲の全体にわたって用いる。特記しない限りは、かかる用語は、当該技術分野におけるそれらの通常の意味を与えるものである。他の具体的に定義された用語は、本明細書に提供された定義と一致するように解釈されるものである。
本明細書に用いた「アルカノイル」とは、「アシル」とも互換的に用いられるが、約1〜約10の炭素原子(さらに、本明細書中の炭素原子の範囲および特定数のすべての組み合わせおよびサブコンビネーション)を有する、所望により置換されていてもよい直鎖状または分岐鎖状の脂肪族アシル残基をいい、約1〜約7の炭素原子が好ましい。アルカノイル基は、特に限定されるものではないが、ホルミル、アセチル、プロピオニル、ブチリル、イソブチリルペンタノイル、イソペンタノイル、2−メチル−ブチル、2,2−ジメチルプロピオニル、ヘキサノイル、ヘプタノイル、オクタノイル等を含む。「低級アルカノイル」なる用語は、約1〜約5の炭素原子(さらに、本明細書中の炭素原子の範囲および特定数のすべての組み合わせおよびサブコンビネーション)を有する、所望により置換されていてもよい直鎖状または分岐鎖状の脂肪族アシル残基をいう。低級アルカノイル基は、特に限定されるものではないが、ホルミル、アセチル、n−プロピオニル、イソ−プロピオニル、ブチリル、イソ−ブチリル、ペンタノイル、イソ−ペンタノイル等を含む。
本明細書に用いた「アルコキシカルボニル」は、アルキルが前記に定義されものである−C(=O)O−アルキル基をいう。
本明細書に用いた「アロイル」は、アリル基が前記に定義されものである−C(=O)−アリール基をいう。例示的なアロイル基はベンゾイルおよびナフトイルを含む。
本発明によれば、C3に結合するコンプスタチンの生物学的および物理化学的特徴についての情報は、親コンプスタチンペプチドと比較してかなり改善した活性を持つ改変したコンプスタチンペプチドを設計するために利用された。いくつかの具体例において、アナログは、コンプスタチンよりも少なくとも300倍大きな活性を有する。他の具体例において、アナログは、実施例に記載したアッセイを利用して比較すると、コンプスタチンより350、400、450、500、550および600倍またはそれを超えて大きな活性を有する。
モノ−Nα−メチル化スキャンを[Tyr4Ala9]−Ac−コンプスタチン(Ac−Ic[CVYQDWGAHRC]T−NH2;配列番号:3)に対して行った。これらのアナログのアッセイ結果に基づいて、13位の選択的なN−メチル化および置換を[Trp(Me)4Ala9]−Ac−コンプスタチン(Ac−Ic[CV(1−MeW)QDWGAHRC]T−NH2;配列番号:4)に行った。選択したアナログは、表面プラズモン共鳴(SPR)および等温滴定熱量測定(ITC)を用いて、さらに特徴付けした。また、分子動態(MD)シミュレーションを行い、親和性の増加の観察のための可能な機序を調べた。
略語. Ac、アセチル基;Acm、アセトアミドメチル;Boc、tert−ブトキシカルボニル;CHARMM、Chemistry at Harvard Macromolecular Mechanics;DCM、ジクロロメタン;DIC、1,3−ジイソプロピルカルボジイミド;DIPEA、N,N−ジイソプロピルエチルアミン;DMF、N,N−ジメチル−ホルムアミド;ELISA、酵素結合免疫吸着定量法;ESI、エレクトロスプレーイオン化;Fmoc、9−フルオレニルメトシキカルボニル;HOAt、1−ヒドロキシ−7−アザ−ベンゾトリアゾール;ITC、等温滴定熱量測定;MALDI、マトリックス支援レーザー脱離イオン化法;MBHA、4−メチルベンズ−ヒドリルアミン;MOE、分子操作環境;NAMD、ナノスケール分子動力学;Nle、L−ノルロイシン;NMP、N−メチルピロリジノン;RMSD、平均二乗偏差;SPR、表面プラズモン共鳴;TIPS、トリイソプロピルシラン;Trt、トリチル。
補体活性化の抑制. 骨格N−メチル化スキャンを[Tyr4Ala9]−Ac−コンプスタチンテンプレート(ペプチド1;配列番号:3)に行い、アナログ2〜13(表1−1)を生成した。ペプチド1は現在のリード化合物[Trp(Me)4 Ala9]−Ac−コンプスタチン(ペプチド14、配列番号:4)より強力ではなかったが、それは、低コストの合成のために最初のスキャンのために選定した。次いで、補体の活性化を抑制する各ペプチドの能力は、ELISAにより評価し、ペプチド1の活性と比較した(表1−1)。最もネガティブな効果は、Val3、Tyr4およびAla9のN−メチル化につき観察し、それはペプチド3、4および9を完全に不活性にした。対照的に、Gly8およびThr13のN−メチル化は、わずかに増加した効力(各々、1.7倍および1.3倍)を持つペプチド8および13を生成した。他のすべての位置のN−メチル化の結果、検知可能だが、まだかなり低減した抑制活性を生じた(表1−1)。
この実施例は、以下に示すアルブミン結合ペプチド(ABP)またはアルブミン結合低分子(ABM)にコンジュゲートした、コンプスタチンアナログ(実施例1に記載したペプチド17:Ac−Ilec[Cys−Val−Trp(Me)−Gln−Asp−Trp−Sar−Ala−His−Arg−Cys]−Ile−NH2;配列番号:7)の合成の改善および血漿中半減期決定を記載する。
略語. Ac、アセチル;Acm、アセトアミドメチル;Acm、アセトアミドメチル;DCM、ジクロロメタン;DIC、1,3−ジイソプロピルカルボジイミド;
DIPEA、N,N−ジイソプロピルエチルアミン;DMF、N,N−ジメチル−ホルムアミド;ELISA、酵素結合免疫吸着定量法;ESI、エレクトロスプレーイオン化;Fmoc、9−フルオレニルメトシキカルボニル;HLB、親水性−親油性バランス;HOAt、1−ヒドロキシ−7−アザ−ベンゾトリアゾール;HSW、Henke Sass Wolf;ITC、等温滴定熱量測定;MALDI、マトリックス支援レーザー脱離イオン化法;MBHA、4−メチルベンズ−ヒドリルアミン;Mmt、モノメトキシトリチル;ナノESI、ナノエレクトロスプレーイオン化;NMP、N−メチルピロリジノン;PyBOP、ベンゾトリアゾール−1−イル−オキシトリピロリジノホスホニウムヘキサフルオロホスフェート;SPR、表面プラズモン共鳴;TBTA、トリス−(ベンジルトリアゾリルメチル)アミン;TEA、トリエチルアミン;TFA、トリフルオロ酢酸;TIP、トリイソプロピルシラン;Trt、トリチル。
DICおよびFmoc−Trp(Me)−OHは、AnaSpec (San Jose, CA)から購入した。低負荷NovaSyn(登録)TGR樹脂および他のFmocアミノ酸は、Novabiochem (San Diego, CA)から得た。ミニ−PEGおよびミニ−PEG−3はPeptide International (Louisville, Kentucky)から購入した。HOAtはAdvanced ChemTech (Louisville, KY)から購入した。ABMはEnamine Ltd. (Kiev, Ukraine)から得た。NMPおよびDCMはFisher Scientific (Pittsburgh, PA)から得た。水はMilli-Q水浄化システム(Millipore Corporate, Billerica, MA)を用いて精製した。合成用の他のすべての化学試薬はSigma-Aldrich (St. Louis, MO)から購入し、さらなる精製なくして用いた。
ペプチドは、分取用RP−HPLCカラム(Xbridge(商標)BEH130 Prep C18 5um 19x150mm, PN# 186003945, Waters, Milford, MA)に注入し、20mL/分間の流量にて15分間にわたり0.1%TFA中の15〜50%のアセトニトリルの直線濃度勾配で溶出させた。所望の生成物を含む画分を質量に基づいて集め、凍結乾燥した。分析用RP−HPLC(Xbridge(商標)BEH130 C18 5um, 4.6x150mm, PN# 186003580, Waters, Milford, MA)により決定した>95%純粋であった。各ペプチドの質量はWaters MALDIマイクロMX装置または SYNAPT HDMSを用いて確認した。
ヒヒ血漿試料(40μL)を内部標準と混合し、40mM炭酸アンモニウム緩衝液で1:1に溶解した。Rapigest洗浄剤を0.1%最終濃度まで添加した。ジスルフィド架橋は60℃にて30分間5mM DTT中で還元した。システインのアルキル化は、15mMの最終濃度までのヨードアセトアミドの添加、および暗所での30分間のインキュベーションにより行った。試料は、16μLの1μg/μLトリプシン溶液の添加および37℃にての一晩のインキュベーションにより酵素的に消化した。その後、試料pHは5% TFAで低下させて、洗浄剤分解を引き起した。非常に疎水性のペプチドの非特異的吸着を回避するために、アセトニトリルを20%まで添加した。試料は6℃および14000rpmにて30分間で遠心分離し、10kDaのカットオフmicrocon遠心フィルター(Millipore, Billerica, MA)での濾過に先立ち、上清を0.1%ギ酸で希釈して、10%までアセトニトリル濃度を低下させた。フィルターは、0.1%ギ酸中の10% ACNの50μLで洗浄し、集めた試料を乾燥まで蒸発させ、0.1%ギ酸中の10%ACNで再構成した。
ペプチド17−ABMの合成. 以下の反応図式に要約されるごとく、ペプチド17−ABMは、固相ペプチド合成およびHPLC精製後に得た。直鎖ペプチドは各アミノ酸の単一カップリングで合成した。タリウムトリフルオロアセテートおよびヨウ素の双方をジスルフィド結合形成につき評価した。前者は、よりきれいな反応を与え、その後、すべての環化に用いた。ペプチド17−ABMの質量は、HPLC−MSおよびESI−TOFにより確認した([MH]2+計算値 1211.05、実測値 1211.06)。
Claims (15)
- Xaa1−Cys−Val−Xaa2−Gln−Asp−Xaa3−Gly−Xaa4−His−Arg−Cys−Xaa5(環状C2−C12)
[式中、8位のGlyをN−メチル化により改変して、その位置にて骨格立体構造を拘束し、
Xaa1は、Ile、Val、Leu、Ac−Ile、Ac−Val、Ac−Leu、またはジペプチドGly−Ileであり;
Xaa2はTrpまたはTrpのアナログであり、ここに、Trpのアナログは、Trpと比較して疎水性特性を増加させ;
Xaa3は、Trp、またはインドール環の水素結合ポテンシャルを増加させる、そのインドール環に対する化学的修飾を含むTrpのアナログであり;
Xaa4は、His、Ala、PheまたはTrpであり;および
Xaa5は、Thr、Ile、Leu、Nle、N−メチルThrまたはN−メチルIleのいずれかのカルボキシ末端の−OHが、−NH2により所望により置換されていてもよいThr、Ile、Leu、Nle、N−メチルThrまたはN−メチルIleである]
である配列番号:2の配列を有するペプチドを含むコンプスタチンアナログ。 - Xaa1がAc−Ileであり、Xaa2が1−メチル−Trpまたは1−ホルミル−Trpであり、Xaa3がTrpであり、Xaa4がAlaであって、Xaa5がThr、Ile、Leu、Nle、N−メチルThrまたはN−メチルIleである請求項1記載のコンプスタチンアナログ。
- Xaa5が、Ile、N−メチルThrまたはN−メチルIleである請求項2記載のコンプスタチンアナログ。
- 配列番号:5、7、8、9、10または11のいずれかを含む請求項2記載のコンプスタチンアナログ。
- さらに、コンプスタチンアナログのin vivo保持を延長するさらなる成分を含む請求項1〜4のいずれか1記載のコンプスタチンアナログ。
- さらなる成分が、ポリエチレングリコール(PEG)である請求項5記載のコンプスタチンアナログ。
- さらなる成分が、アルブミン結合低分子である請求項5記載のコンプスタチンアナログ。
- アルブミン結合低分子が、コンプスタチンアナログの末端に結合している請求項7記載のコンプスタチンアナログ。
- さらなる成分が、アルブミン結合ペプチドである請求項5記載のコンプスタチンアナログ。
- アルブミン結合ペプチドが、配列RLIEDICLPRWGCLWEDD(配列番号:14)を含む請求項9記載のコンプスタチンアナログ。
- アルブミン結合ペプチドに結合した配列番号:5、7、8、9、10または11のいずれか1つを含む請求項9記載のコンプスタチンアナログ。
- 化合物およびアルブミン結合ペプチドがスペーサーにより分離される請求項9記載のコンプスタチンアナログ。
- スペーサーがポリエチレングリコール分子である請求項12記載のコンプスタチンアナログ。
- 前記請求項1〜13のいずれか1記載のコンプスタチンアナログおよび医薬上許容される担体を含む医薬組成物。
- 補体活性化の抑制のための医薬製造における前記請求項1〜13のいずれか1記載のコンプスタチンアナログの使用。
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PL2424557T3 (pl) | 2018-04-30 |
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US8946145B2 (en) | 2015-02-03 |
AU2010242739B2 (en) | 2016-08-25 |
WO2010127336A1 (en) | 2010-11-04 |
CA2760839C (en) | 2019-02-12 |
PT2424557T (pt) | 2018-02-05 |
JP6106731B2 (ja) | 2017-04-05 |
JP2012525443A (ja) | 2012-10-22 |
ES2655389T3 (es) | 2018-02-19 |
EP2424557B1 (en) | 2017-10-25 |
HUE035378T2 (en) | 2018-05-02 |
CA2760839A1 (en) | 2010-11-04 |
JP5882890B2 (ja) | 2016-03-09 |
US9371365B2 (en) | 2016-06-21 |
NO2424557T3 (ja) | 2018-03-24 |
AU2010242739A1 (en) | 2011-12-08 |
EP2424557A1 (en) | 2012-03-07 |
CN102458438A (zh) | 2012-05-16 |
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