JP4425154B2 - 機能性物質の構造決定方法および製造方法 - Google Patents
機能性物質の構造決定方法および製造方法 Download PDFInfo
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Description
本発明に係る標的としては、特に制限はなく、目的に応じて適宜選択することができ、たとえば、タンパク質、リポタンパク質、糖タンパク質、ポリペプチド、脂質、多糖類、リポ多糖類、核酸、環境ホルモン、薬物、これらの複合体などが挙げられる。
本発明に係る機能性物質は標的に対し親和性を有する物質である。増幅されるべき機能性物質は、その内、その有するいずれかの置換基を脱離すれば、何らかの方法により増幅できる物質である。本発明により製造される機能性物質は、増幅されるべき機能性物質またはその分解物、あるいは、増幅されるべき機能性物質またはその分解物を含む物質を意味する。
機能性物質には、標的との親和性を高める、安定性を高める、合成を容易にする等の種々の理由から種々の置換基が導入される。
本発明に係る機能性物質候補には特に制限はなく、どのようなものを選択してもよいが、たとえば、目的として考えている機能性物質を合成できるであろうと考える原料組成から合成された物質のグループを挙げることができる。この場合、原料の一つとして特定の置換基を有する物質を使用すれば、特定の置換基を有する物質のグループを得ることができる。機能性物質候補の数には特に制限はない。何千、何万の機能性物質候補の中からたった一つの機能性物質を選別することもあり得る。
本発明に係る選別としては、特に制限はなく、目的に応じて適宜選択することができる。修飾ヌクレオチド配列を含んでなる機能性物質の場合には、たとえば、アフィニティークロマトグラフィー、フィルター結合、液−液分割、ろ過、ゲルシフト、密度勾配遠心分離などの各種方法が挙げられる。これらは、1種単独で行ってもよく、2種以上行ってもよい。これらの中でも、アフィニティークロマトグラフィーが好ましい。選別される機能性物質は1種類ではなく複数種類であることもあり得る。
本発明に係る増幅は、特定の基を脱離したあとの機能性物質を増幅できるものであればどのような方法でもよく、公知の方法の中から適宜選択することができるが、機能性物質がヌクレオチド配列を含んでなる場合には、PCR法、LCR(Ligase chain Reaction)法、3SR(Self−sustained Sequence Replication)法、SDA(Strand Displacement Amplification)法、RT−PCR法、ICAN法、LAMP法などが挙げられる。これらは、1種単独で行ってもよいし、2種以上行ってもよい。これらの中でもPCR法が好ましい。
本発明に係る機能性物質の構造決定の方法については特に制限はなく、公知のどのような方法を採用してもよい。本発明に係る機能性物質の構造決定における「構造の決定」には原子配列等のどのような構造の決定を含めてもよいが、機能性物質がヌクレオチド配列を含んでなる場合の典型例は、このヌクレオチド配列の決定を意味する。
本発明に係る特定の置換基の脱離には特に制限はなく、公知のどのような方法を採用することもできる。シスジオールの過ヨウ素酸酸化による切断、シリル基のフッ素イオンによる切断、酸アルカリによる切断、酵素反応による切断または光反応による切断を例示することができる。
以上の機能性物質の構造決定方法を利用すれば、その後、この機能性物質を容易に製造することができる。この製造段階に使用できる方法については特に制限はなく、公知のどのような方法を採用することもできる。たとえばヌクレオチド配列を含んでなる機能性物質の場合には、機能性物質候補について説明したのと同様の方法を利用することができる。この場合には、原料組成を選択することにより、機能性物質を収率よく製造することが可能である。
(構造決定方法および製造方法の例)
本発明に係る構造決定方法および製造方法を図3を使用して例示する。図3の(1)は、本発明に係る機能性物質候補のグループを表す模式図である。機能性物質候補として修飾ヌクレオチド配列を使用している。
(DNA増幅酵素により認識されない塩基を含む場合の増幅)
本実施例では、DNA配列ttatcaacaaaatactccaattgN50gaaagatcccaacgaaaagの配列をDNA自動合成機(アプライド391A)で合成した。
(置換基の脱離)
dACGT”Tの配列を持つDNA配列を、dA,dC,dG,dT,dT”のアミダイトを用いて合成し、一部をフォスフォジエステラーゼ+アルカリフォスファターゼにより、モノマーまで分解し、HPLC分析により標品と比較した結果、アミノ基は生成しておらず、保護基が脱離されていないことを確認した。
(置換基が切断されたDNAのDNAポリメレース寛容性の確認)
dT”の置換基が切断された5−プロパルギルアミノdUを通常の保護条件(濃アンモニア水で、55℃下、8時間)で生成するdT’’’アミダイトを用い、DNA自動合成機を使用して、ttatcaacaaaatactccaattggcgatggccctgtccdT’’’ dT’’’adT’’’accagacaaccattacctgtccacacaatctgccctttcgaaagatcccaacgaaaagの配列を合成した。
(置換基の脱離)
dACGT””Tの配列を持つDNA配列を、dA,dC,dG,dT,dT””のアミダイトを用いて合成し、一部をフォスフォジエステラーゼ+アルカリフォスファターゼにより、モノマーまで分解し、HPLC分析により標品と比較した結果、アミノ基は生成しておらず、本発明に係る置換基が脱離されていないことを確認した。図8にdT””のBaseの構造を示す。
(置換基の脱離)
dACGT””’Tの配列を持つDNA配列を、dA,dC,dG,dT,dT””’のアミダイトを用いて合成し、一部をフォスフォジエステラーゼ+アルカリフォスファターゼにより、モノマーまで分解し、HPLC分析により標品と比較した結果、アミノ基は生成しておらず、本発明に係る置換基が脱離されていないことを確認した。図9にdT””のBaseの構造を示す。
標的に対し親和性を有する物質(機能性物質)の候補を合成し、
当該機能性物質候補の中から、標的に対し親和性を有する機能性物質を選別し、
当該選別された機能性物質から特定の置換基を脱離し、
当該特定の置換基を脱離した機能性物質を増幅し、
当該増幅された機能性物質の構造を決定する、
機能性物質の構造決定方法。
前記特定の置換基が、置換基を有していてもよい、天然または非天然のアミノ酸基、金属錯体基、蛍光色素基、酸化還元色素基、スピンラベル化が可能な基、炭素数1〜10のアルキル基および、式(1)〜(10)で表される基からなる群から選ばれた少なくとも一つの基を有する、付記1に記載の機能性物質の構造決定方法。
シスジオールの過ヨウ素酸酸化による切断、シリル基のフッ素イオンによる切断、酸アルカリによる切断、酵素反応による切断または光反応による切断により、前記特定の置換基を機能性物質から脱離する、付記1または2に記載の機能性物質の構造決定方法。
前記機能性物質が、修飾ヌクレオチド配列を含んでなる、付記1〜3のいずれかに記載の機能性物質の構造決定方法。
前記機能性物質が、修飾DNA配列または修飾RNA配列である、付記1〜4のいずれかに記載の機能性物質の構造決定方法。
前記標的が、タンパク質、リポタンパク質、糖タンパク質、ポリペプチド、脂質、多糖類、リポ多糖類、核酸、環境ホルモン、薬物、これらの複合体およびこれらの分解物からなる群から選択される少なくとも一つの物質である、付記1〜5のいずれかに記載の機能性物質の構造決定方法。
標的に対し親和性を有する物質(機能性物質)の候補を合成し、
当該機能性物質候補の中から、標的に対し親和性を有する機能性物質を選別し、
当該選別された機能性物質から特定の置換基を脱離し、
当該特定の置換基を脱離した機能性物質を増幅し、
当該増幅された機能性物質の構造を決定し、
当該構造に基づいて、機能性物質を製造する
機能性物質の製造方法。
前記特定の置換基が、置換基を有していてもよい、天然または非天然のアミノ酸基、金属錯体基、蛍光色素基、酸化還元色素基、スピンラベル化が可能な基、炭素数1〜10のアルキル基および、式(1)〜(10)で表される基からなる群から選ばれた少なくとも一つの基を有する、付記7に記載の機能性物質の製造方法。
シスジオールの過ヨウ素酸酸化による切断、シリル基のフッ素イオンによる切断、酸アルカリによる切断、酵素反応による切断または光反応による切断により、前記特定の置換基を機能性物質から脱離する、付記7または8に記載の機能性物質の製造方法。
前記機能性物質が、修飾ヌクレオチド配列を含んでなる、付記7〜9のいずれかに記載の機能性物質の製造方法。
前記機能性物質が、修飾DNA配列または修飾RNA配列である、付記7〜10のいずれかに記載の機能性物質の製造方法。
前記標的が、タンパク質、リポタンパク質、糖タンパク質、ポリペプチド、脂質、多糖類、リポ多糖類、核酸、環境ホルモン、薬物、これらの複合体およびこれらの分解物からなる群から選択される少なくとも一つの物質である、付記7〜11のいずれかに記載の機能性物質の製造方法。
2 ヌクレオチド固定配列部分
3 ヌクレオチド固定配列部分
4 修飾ヌクレオチド配列部分
5 アフィニティーカラム
6 遊離した機能性物質
7 ノズル
Claims (5)
- 修飾DNA配列または修飾RNA配列を有し標的に対し親和性を有する物質であって、増幅の進行を妨げる特定の置換基を含む機能性物質の候補を合成し、
当該機能性物質候補の中から、修飾DNA配列または修飾RNA配列を有し標的に対し親和性を有する機能性物質を選別し、
シスジオールの過ヨウ素酸酸化による切断、シリル基のフッ素イオンによる切断、酸アルカリによる切断、酵素反応による切断または光反応による切断により、当該選別された機能性物質から特定の置換基を脱離し、
当該特定の置換基を脱離した機能性物質を増幅し、
当該増幅された機能性物質の構造を決定する、
機能性物質の構造決定方法。 - 修飾DNA配列または修飾RNA配列を有し標的に対し親和性を有する物質であって、増幅の進行を妨げる特定の置換基を含む機能性物質の候補を合成し、
当該機能性物質候補の中から、修飾DNA配列または修飾RNA配列を有し標的に対し親和性を有する機能性物質を選別し、
シスジオールの過ヨウ素酸酸化による切断、シリル基のフッ素イオンによる切断、酸アルカリによる切断、酵素反応による切断または光反応による切断により、当該選別された機能性物質から特定の置換基を脱離し、
当該特定の置換基を脱離した機能性物質を増幅し、
当該増幅された機能性物質の構造を決定する、
機能性物質の構造決定方法であって、
前記特定の置換基が、置換基を有していてもよい、天然または非天然のアミノ酸基、金属錯体基、蛍光色素基、酸化還元色素基、スピンラベル化が可能な基、炭素数1〜10のアルキル基および、式(1)〜(10)で表される基からなる群から選ばれた少なくとも一つの基を有する機能性物質の構造決定方法。
- 修飾DNA配列または修飾RNA配列を有し標的に対し親和性を有する物質であって、増幅の進行を妨げる特定の置換基を含む機能性物質の候補を合成し、
当該機能性物質候補の中から、修飾DNA配列または修飾RNA配列を有し標的に対し親和性を有する機能性物質を選別し、
シスジオールの過ヨウ素酸酸化による切断、シリル基のフッ素イオンによる切断、酸アルカリによる切断、酵素反応による切断または光反応による切断により、当該選別された機能性物質から特定の置換基を脱離し、
当該特定の置換基を脱離した機能性物質を増幅し、
当該増幅された機能性物質の構造を決定し、
当該構造に基づいて、機能性物質を製造する
機能性物質の製造方法。 - 修飾DNA配列または修飾RNA配列を有し標的に対し親和性を有する物質であって、増幅の進行を妨げる特定の置換基を含む機能性物質の候補を合成し、
当該機能性物質候補の中から、修飾DNA配列または修飾RNA配列を有し標的に対し親和性を有する機能性物質を選別し、
シスジオールの過ヨウ素酸酸化による切断、シリル基のフッ素イオンによる切断、酸アルカリによる切断、酵素反応による切断または光反応による切断により、当該選別された機能性物質から特定の置換基を脱離し、
当該特定の置換基を脱離した機能性物質を増幅し、
当該増幅された機能性物質の構造を決定し、
当該構造に基づいて機能性物質を製造する
機能性物質の製造方法であって、
前記特定の置換基が、置換基を有していてもよい、天然または非天然のアミノ酸基、金属錯体基、蛍光色素基、酸化還元色素基、スピンラベル化が可能な基、炭素数1〜10のアルキル基および、式(1)〜(10)で表される基からなる群から選ばれた少なくとも一つの基を有する機能性物質の製造方法。
- 前記標的が、タンパク質、リポタンパク質、糖タンパク質、ポリペプチド、脂質、多糖類、リポ多糖類、核酸、環境ホルモン、薬物、これらの複合体およびこれらの分解物からなる群から選択される少なくとも一つの物質である、請求項4に記載の機能性物質の製造方法。
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