JP2007289153A - 機能性分子およびその製造方法 - Google Patents
機能性分子およびその製造方法 Download PDFInfo
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- JP2007289153A JP2007289153A JP2007064602A JP2007064602A JP2007289153A JP 2007289153 A JP2007289153 A JP 2007289153A JP 2007064602 A JP2007064602 A JP 2007064602A JP 2007064602 A JP2007064602 A JP 2007064602A JP 2007289153 A JP2007289153 A JP 2007289153A
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Abstract
【解決手段】本機能性分子の製造方法には、所定の条件で切断可能な部位である切断可能リンカーを有する特定物質をレジンに結合させて特定物質結合レジンを作製し、機能性分子候補を含む溶液でこの特定物質結合レジンを処理し、ついで、所定の条件で切断可能リンカーを切断し、特定物質と特異的に相互作用した機能性分子を選別することが含まれる。
【選択図】なし
Description
機能性分子候補を含む溶液で当該特定物質結合レジンを処理し、
ついで、前記所定の条件で切断可能リンカーを切断し、当該特定物質と特異的に相互作用した機能性分子を選別することを含む、機能性分子の製造方法
が提供される。
なお、3量体以上の修飾ヌクレオチドn量体についても同様の方法で作製することができる。nの上限については特に制限はなく、いわゆるオリゴマーからポリマーまでを包含し得る。n=10〜50が好ましい場合が多い。
(DNAランダムミックスの作成)
DNAランダムミックスは、先願と同様の手法で合成した。具体的には、tta tcaacaaaat actccaattg (NpNp)25ga aagatcccaacgaaaag構造のDNAランダムミックスをDNA自動合成機(アプライド391A)で合成した。NpNp部分は、表1の組み合わせを持つダイマーアミダイドの混合物(ランダムミックス)を用いることにより合成したものである。表1中、斜線の入った部分の組み合わせは含まれていない。なお、図7には、表1中の各略号で表される構造を纏めてある。図7の見方は次の通りである。すなわち、図7の左上には表1に係るダイマーアミダイドの構造が示されているが、その3’Baseと5’BaseとにA,G,C,T,Xの構造が入る。LysはXで表される構造中のRが、図1中のLys:Rで表された構造を有することを意味する。Tyr,Trp,Leu,Glu,Phe,Serについても同様である。図7を参照して、表1では、たとえば、3’のAと5’のXとが交差する欄にLysと記載されているが、このことは、図7の左上のダイマーアミダイド構造において、その3’Baseが図7のAの構造を有し、その5’Baseが、図7のXの構造を有し、そのXにおいて、そのRがLysの構造を有することを意味する。
ビオチン化修飾され、このビオチン化修飾された部位とタンパク質本体との間にエンテロキナーゼ切断部位(本発明に係る切断可能リンカーに該当)を持つGFP(Green Fluorescent Protein:緑色蛍光タンパク質)溶液をストレプトアビジンレジンに湿潤させ、洗浄することによりGFP結合レジンを作成した。
遺伝子操作により部位特異的にシステイン残基を導入したGFPを、下記式の、ビオチン化修飾されかつ末端マレイミド修飾されたDNAと反応させ、このDNA(本発明に係る切断可能リンカーに該当)と結合したGPF−DNA錯体を単離した。
(DNAランダムミックスの作成)
DNAランダムミックスは、実施例1と同じ手法で合成した。具体的には、5’−gaaggtgaaggtcggagtcaacg((NPNP)g/c)7gct((NPNP)g/c)7ggaaatcccatcaccatcttc−3’構造のDNAランダムミックスをDNA自動合成機で合成した。NpNp部分は、dALeu−dA、dAPhe−dC、dAGlu−dT、dGly−dC、dT−dALysのいずれかである。ここで、たとえばdALeu−dAは、図7の左上の構造において、5’BaseがAであり、3’BaseがXであり、そのRがLeuであることを意味する。
複合体レジンを、20mMのTris−HCl(pH7.4)、50mMのKCl、2mMのCaCl2で平衡化した後に、エンテロキナーゼ1ユニットを加え20℃で一晩反応させた。反応終了後、溶液をフィルターろ過することにより、レジンと修飾核酸−GFP複合体を分離し、回収した。
GFPに対する結合解離定数(KD)は、水晶発振子を利用した水晶マイクロ質量計(イニシアム社製)を用いて得た、飽和法による平衡解析測定結果を、AQUA(イニシアム社製)ソフトウエアにより処理することで決定した。
Claims (10)
- 所定の条件で切断可能な部位である切断可能リンカーを有する特定物質をレジンに結合させて特定物質結合レジンを作製し、
機能性分子候補を含む溶液で当該特定物質結合レジンを処理し、
ついで、前記所定の条件で切断可能リンカーを切断し、当該特定物質と特異的に相互作用した機能性分子を選別することを含む、機能性分子の製造方法。 - 前記特定物質が、タンパク質、リポタンパク、糖タンパク、ポリペプチド、脂質、多糖類、リポ多糖類、核酸および薬物から選ばれる少なくとも1種の物質に由来するものである、請求項1に記載の製造方法。
- 前記特定物質がタンパク質に由来するものである、請求項2に記載の製造方法。
- 前記機能性分子が、核酸もしくは修飾核酸である、請求項1〜3のいずれかに記載の製造方法。
- 前記機能性分子が、核酸を構成するヌクレオシドに置換基が導入された修飾ヌクレオシドを含む修飾ヌクレオチドn量体(n≧2)である、請求項4に記載の製造方法。
- 前記置換基を化学処理により脱離した場合に、前記機能性分子が核酸に転換され得るものである、請求項5に記載の製造方法。
- 前記化学処理がアルカリ処理である、請求項6に記載の製造方法。
- 前記切断可能リンカーが、50℃以下、pH6.0〜9.0の範囲で切断可能である、請求項1〜7のいずれかに記載の製造方法。
- 前記切断可能リンカーが、ジスルフィド結合または隣接ジオール結合を有しもしくは光で切断可能であるか、制限酵素で切断可能な核酸配列であるか、または、酵素で切断可能なアミノ酸配列である、請求項1〜8のいずれかに記載の製造方法。
- 請求項1〜9の方法によって得られる機能性分子。
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JPS60244300A (ja) * | 1984-05-07 | 1985-12-04 | アライド―シグナル・インコーポレーテッド | 組換えタンパク質を用いる置換ポリヌクレオチド検定および診断用キツド |
JP2002510505A (ja) * | 1998-04-03 | 2002-04-09 | フィロス インク. | 位置特定可能な蛋白質アレイ |
JP2002525288A (ja) * | 1998-08-27 | 2002-08-13 | バイエル コーポレイション | 2重末端選択を用いるオリゴマーの精製 |
WO2004018081A1 (ja) * | 2002-08-21 | 2004-03-04 | Tokyo University Of Agriculture And Technology Tlo Co., Ltd. | 電解切断性アフィニティー担体を用いる生体物質の精製法、電解切断性アフィニティー担体、生体物質精製用キット、電解切断性リンカー |
JP2004533608A (ja) * | 2001-03-30 | 2004-11-04 | ザ・トラスティーズ・オブ・コランビア・ユニバーシティー・イン・ザ・シティー・オブ・ニューヨーク | 固相捕獲可能なジデオキシヌクレオチドおよび質量分析を使用する高い忠実度のdnaシーケンシング |
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DK0786469T3 (da) * | 1990-06-11 | 2006-07-10 | Gilead Sciences Inc | Nukleinsyreligander |
US5723289A (en) * | 1990-06-11 | 1998-03-03 | Nexstar Pharmaceuticals, Inc. | Parallel selex |
US5597909A (en) | 1994-08-25 | 1997-01-28 | Chiron Corporation | Polynucleotide reagents containing modified deoxyribose moieties, and associated methods of synthesis and use |
WO1998008856A2 (de) * | 1996-08-30 | 1998-03-05 | Fuerste Jens Peter | Spiegelselektion und spiegelevolution von nucleinsäuren |
US6218530B1 (en) * | 1998-06-02 | 2001-04-17 | Ambergen Inc. | Compounds and methods for detecting biomolecules |
US20040197841A1 (en) * | 2003-04-02 | 2004-10-07 | Apffel James Alexander | Methods and reagents for multiplexed analyses |
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JPS60244300A (ja) * | 1984-05-07 | 1985-12-04 | アライド―シグナル・インコーポレーテッド | 組換えタンパク質を用いる置換ポリヌクレオチド検定および診断用キツド |
JP2002510505A (ja) * | 1998-04-03 | 2002-04-09 | フィロス インク. | 位置特定可能な蛋白質アレイ |
JP2002525288A (ja) * | 1998-08-27 | 2002-08-13 | バイエル コーポレイション | 2重末端選択を用いるオリゴマーの精製 |
JP2004533608A (ja) * | 2001-03-30 | 2004-11-04 | ザ・トラスティーズ・オブ・コランビア・ユニバーシティー・イン・ザ・シティー・オブ・ニューヨーク | 固相捕獲可能なジデオキシヌクレオチドおよび質量分析を使用する高い忠実度のdnaシーケンシング |
WO2004018081A1 (ja) * | 2002-08-21 | 2004-03-04 | Tokyo University Of Agriculture And Technology Tlo Co., Ltd. | 電解切断性アフィニティー担体を用いる生体物質の精製法、電解切断性アフィニティー担体、生体物質精製用キット、電解切断性リンカー |
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