JP2005176858A - 自己消光性蛍光プローブと方法 - Google Patents
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Abstract
【解決手段】 自分自身とハイブリダイズしてヘアピン構造を形成しないオリゴヌクレオチド配列、該オリゴヌクレオチド配列に結合した蛍光報知分子及び該蛍光報知分子の蛍光を消光できる消光分子を含むオリゴヌクレオチドプローブであって、ハイブリダイズしていないときは少なくとも一本鎖構造で存在することができ、この場合、当該消光分子は該報知分子の蛍光を消光し、標的ポリヌクレオチドとハイブリダイズしているときは少なくとも1つの構造で存在することができ、この場合、該報知分子の蛍光は消去されず、該オリゴヌクレオチド配列が該標的ポリヌクレオチドとハイブリダイズしているときに最大発光の該報知分子の蛍光強度は、該オリゴヌクレオチド配列が該標的ポリヌクレオチドとハイブリダイズしていないときに最大発光の当該報知分子の蛍光強度よりも少なくとも6倍強いオリゴヌクレオチドプローブ。
【選択図】 なし
Description
本明細書で用いられるように、報知分子は蛍光シグナルを発生させることができる分子である。消光分子は、励起した報知分子の蛍光エネルギーを吸収し、それによって本来ならば励起した報知分子から遊離されるはずであった蛍光シグナルを消光させることができる分子である。消光分子が励起した発蛍光団を消光させるためには該消光分子は、蓄積された蛍光エネルギーを報知分子が遊離する前のある時期に励起報知分子について最小消光距離内に存在しなければならない。
報知分子−消光分子対を含むプローブがハイブリダイゼーションアッセー用に開発されたが、この場合該プローブはヘアピン構造を形成する。すなわちこの場合には、該プローブは、ヘアピン構造の形成を妨げる相補的核酸配列が存在しないときそれ自身とハイブリダイズし、該報知分子の近傍に消光分子が配置されるようなループを形成する(WO90/03446;欧州特許出願公開公報第0601889A2号)。相補的な標的配列が存在する場合、該相補的標的配列へのプローブのハイブリダイゼーションによってヘアピン構造が破壊され、該消光分子が該報知分子にもはや十分に接近できず該報知分子を消光することができない構造をこのプローブに受容させる。結果として、該プローブは、標的配列とハイブリダイズした場合はハイブリダイズしない場合よりも強い蛍光シグナルをもたらす。ヘアピン構造を含むプローブは、そのようなプローブはデザインが困難であるということ、さらに標的配列とプローブとのハイブリダイゼーションに干渉する可能性があるという欠点をもつ。
報知分子−消光分子対を含むプローブの特に重要な応用の1つは、核酸増幅反応(例えばポリメラーゼ連鎖反応(PCR))で標的核酸配列の存在および増幅を検出するためにそれらを使用することである。一般に、核酸増幅技術は遺伝学的検査およびDNA分析に通じる幅広い新規な研究方法を提供した(Arnheim & Erlich,Ann.Rev.Biochem.,61:131-156(1992))。特にPCRは、例えばクローニング、遺伝的発現の分析、DNA配列決定、遺伝学地図の作製および薬剤の発見の分野で応用される極めて重要な研究手段となった(Arnheim & Erlich,Ann.Rev.Biochem.,61:131-156(1992);Gillilandら、Proc.Natl.Acad.Sci.,87:2725-2729(1990);Bevanら、PCR Methods and Applications,1:222-228(1992);Green ら、PCR Methods and Applications,1:77-90(1991); Blackwellら、Science,250:1104-1110(1990))。
核酸増幅技術の利用の広がりによって、様々な環境下で増幅反応を実施するための手段の開発が促進された。そのような機器の開発で重要なデザイン目標には、精密な温度制御、多サンプル用温度循環におけるサンプル間変動の最小化、反応前および反応後処理工程の自動化、高速温度循環、サンプル量の最小化、増幅生成物のリアタイム測定および交差夾雑の最小化(例えば“サンプルの持ち越し”のために生じる)が含まれる。特に、閉鎖反応チャンバーでの増幅の実施およびリアルタイムモニターを可能にする機器のデザインは、交差夾雑を防ぐために大いに望まれるところである(Higuchiら、Biotechnology,10:413-417(1992)および11:1026-1030(1993);Hollandら、Proc.Natl.Acad.Sci.,88:7276-7280(1991))。明らかに、そのようなデザイン目標の達成は、例えば“サンプル持ち越し”のために生じる高頻度の偽陽性および偽陰性が増幅処理の意義を大きく減退させる診断用サンプルの分析で特に望まれる。のみならず、増幅反応をリアルタイムでモニターすることによって多重標的増幅反応における出発標的DNA濃度のはるかに正確な定量が可能になる。なぜならば、反応時の相対濃度値の流れを考慮することによって近似濃度の相対値を解析することができるからである。リアルタイムモニタリングはまた増幅反応効率の評価を可能にするが、これによって反応抑制物がサンプル中に存在するか否かが示される。
図1に示すTaq−Manアプローチは、標的ポリヌクレオチドの“下流領域”(すなわちプライマー結合部位の伸長方向)に特異的にやきもどし(アニール)される報知分子−消光分子対を含むオリゴヌクレオチドプローブを用いる。この報知分子および消光分子は互いに十分接近して配置され、それによって報知分子が励起されると常にこの励起状態エネルギーは消光分子に非放射性に伝えられ、該エネルギーは非放射性に消失するか、または報知分子の発光周波数と異なる周波数で放出される。DNAポリメラーゼによって鎖が伸長している間プローブは鋳型とアニールし、このプローブはポリメラーゼの5’→3’エクソヌクレアーゼ活性によって消化される。プローブが消化される結果、この報知分子は効果的に消光分子から分離され、それによって消光分子はもはや報知分子の蛍光を消光できるほど十分に報知分子に接近することができない。したがって、増幅時にプローブが消化されればされるほど、溶液中の報知分子数は増加し、結果として非消光報知分子数が増す結果となり蛍光シグナルはますます強くなる。
すなわち、RQ-は、オリゴヌクレオチドプローブが一本鎖状態の場合の消光分子の蛍光に対する報知分子の蛍光放出の比である。RQ-値に対する影響は、例えば、用いられる特定の報知分子および消光分子、報知分子と消光分子との間の間隔の取り方、ヌクレオチド配列特異的効果、報知分子と消光分子が結合している構造物(例えばリンカー)の可撓性の度合い、および不純物の存在を含む(Woら、Anal.Biochem.,218:1-13(1994); Clegg,Meth.Enzymol.,211:353-388(1992))。相対量RQ+は、オリゴヌクレオチドプローブが相補的ポリヌクレオチドとハイブリダイズしたときの消光分子に対する報知分子の蛍光放出比を指す。
第二の要因はプローブが相補的ポリヌクレオチドとハイブリダイズする効率である。この第二の要因は、プローブの融解温度(Tm)、プローブまたは標的ポリヌクレオチドの二次構造の有無、アニーリングの温度および他の反応条件に左右される。
第三の要因は、DNAポリメラーゼの5’→3’エクソヌクレアーゼ活性が結合プローブを報知分子と消光分子との間で切断する効率である。この効率は、報知分子または消光分子のプローブの5’末端との近さ、報知分子または消光分子の“かさ(bulkiness)”およびプローブと標的ポリヌクレオチドとの相補性の度合いに左右される(Leeら、Nucleic Acids Research,21:3761-3766(1993))。
消光は報知分子と消光分子との物理的近さに左右されるので、以前は、該消光分子が報知分子を消光できる最大の距離(これは一般には約6−16ヌクレオチド)を越えずに常に消光分子が存在するように、消光分子と報知分子がプローブに結合している必要があると考えられていた(Leeら、Nucleic Acids Research,22:920-928(1994); Cardulloら、Proc.Natl.Acad.Sci.,85:8790-8794(1988);Cleggら、Proc.Natl.Acad.Sci.,90:2994-2998(1993);Ozakiら、Nucleic Acids Research,20:5250-5214(1992))。報知分子と消光分子との間のこの短い分離は、典型的には、1組の報知分子−消光分子対をプローブの3’または5’末端に結合させ、さらに他の組を6−16ヌクレオチド離れた内部塩基に結合させることによって達成できる。
内部塩基に報知分子または消光分子を結合させることに付随する少なくとも2つの重大な短所が存在する。報知分子または消光分子を内部ヌクレオチドに結合させることは、末端ヌクレオチドに分子を結合させる場合に必要とされるよりももっと困難な化学操作を必要とする。さらに、報知分子または消光分子の内部ヌクレオチドとの結合はプローブのハイブリダイゼーション効率に悪影響を及ぼすであろう(Wardら、米国特許第5328824号;Ozakiら、Nucleic Acids Research,20:5250-5214(1992))。
本発明にしたがえば、プローブが標的ポリヌクレオチドとハイブリダイズするとき、報知分子の蛍光強度は好ましくは消光分子の蛍光強度よりも大きい。より好ましくは、プローブが標的ポリヌクレオチドとハイブリダイズするとき、報知分子の蛍光強度は消光分子の蛍光強度よりも少なくとも約3.5倍大きい。
好ましくはまた、標的ポリヌクレオチドとハイブリダイズしたオリゴヌクレオチドプローブの蛍光強度は、標的とハイブリダイズしないときのオリゴヌクレオチドプローブの蛍光強度より係数で少なくとも約6倍強い。
報知分子は、消光分子から好ましくは少なくとも約15ヌクレオチド、より好ましくは少なくとも約18ヌクレオチド離れている。報知分子は、好ましくは約15から60ヌクレオチド、より好ましくは約18から30ヌクレオチド消光分子から離れている。
報知分子は好ましくはフルオレセイン染料であり、消光分子は好ましくはローダミン染料である。
ある実施態様では、本発明のオリゴヌクレオチドプローブは固形支持体に固定されている。このオリゴヌクレオチドプローブは固形支持体に、例えば該固形支持体へのプローブの3’または5’末端ヌクレオチドの結合によって直接結合させてもよい。しかしながら、より好ましくは、プローブはリンカーによって固形支持体に結合される。このリンカーは固形支持体からプローブを遠ざけるために役立つ。最も好ましくは、リンカーは長さが少なくとも30原子、より好ましくは長さが少なくとも50原子である。
オリゴヌクレオチドプローブを固形支持体に結合させるために用いられる多様なリンカーが当該技術分野で知られている。最も好ましくは、該リンカーは官能基付加ポリエチレングリコールを含むが、その理由は、標的オリゴヌクレオチドとプローブとのハイブリダイゼーションに著しい干渉を示さないこと、市販されていること、有機および水性媒体の両方に可溶であること、官能基の付加が容易なこと、さらにオリゴヌクレオチド合成条件と合成後条件の下で全く安定であることである。
好ましくは、固形支持体、リンカーおよびプローブ間の連結は、高温の塩基性条件下での塩基保護基の除去時に切断されない。好ましい連結の例にはカルバメートおよびアミド連結が含まれる。
本発明はまた、標的ポリヌクレオチドを検出するためにハイブリダイゼーションプローブとしてオリゴヌクレオチドプローブを使用することに関する。したがって、本発明は、サンプル中の標的ポリヌクレオチドの有無を検出するハイブリダイゼーションアッセーに関する。本方法のある実施態様では、該ハイブリダイゼーションプローブは固形支持体に固定される。
サンプルと接触させる前および後での報知分子の蛍光シグナルが比較される。プローブ上の報知分子は標的配列とハイブリダイズしたときにより強い蛍光シグナルを示すので、サンプルとプローブが接触した後蛍光シグナルの増加があれば、サンプル中の標的配列とプローブとのハイブリダイゼーションが示唆され、したがってサンプル中に標的配列が存在することが示唆される。サンプルとプローブとの接触の結果として、蛍光強度の変化の定量がサンプルに存在する標的配列の量を定量するために用いられる。
本発明はまた、核酸増幅をモニターするために該オリゴヌクレオチドプローブを使用することに関する。したがって、本発明は、5’→3’ヌクレアーゼ活性をもつ核酸ポリメラーゼ、標的配列とハイブリダイズすることができるプライマー、およびプライマーに対して3’側で標的配列とハイブリダイズすることができる本発明のオリゴヌクレオチドプローブを用いて標的配列で核酸増幅を実施することによって核酸増幅をモニターする方法に関する。本発明にしたがえば、この核酸ポリメラーゼは、オリゴヌクレオチドプローブが標的配列とハイブリダイズするとき、増幅時に該オリゴヌクレオチドプローブを消化し、それによって報知分子を消光分子から分離させる。増幅が進行している時に報知分子の蛍光がモニターされ、蛍光の発生は核酸増幅に対応する。したがって、実際の増幅量は観察された蛍光の変化によって定量できる。消光分子の蛍光もまた、別個にまたは報知分子と合わせて増幅検出のためにモニターできることを特記する。
本発明にしたがえば、プローブが標的ポリヌクレオチドとハイブリダイズするときは、好ましくは報知分子の蛍光強度は消光分子の蛍光強度よりも強い。より好ましくは、プローブが標的ポリヌクレオチドとハイブリダイズするときは、報知分子の蛍光強度は消光分子の蛍光強度より係数で少なくとも約3.5倍強い。
標的ポリヌクレオチドとハイブリダイズしたオリゴヌクレオチドプローブの蛍光強度はまた、標的ポリヌクレオチドとハイブリダイズしていないときのオリゴヌクレオチドプローブの蛍光強度より係数で好ましくは少なくとも約6倍強い。
報知分子は、消光分子から好ましくは少なくとも約15ヌクレオチド、より好ましくは少なくとも約18ヌクレオチド離れている。報知分子は、好ましくは約15から60ヌクレオチド、より好ましくは約18から30ヌクレオチド消光分子から離れている。
報知分子は好ましくはフルオレセイン染料で、消光分子は好ましくはローダミン染料である。
ある実施態様では、オリゴヌクレオチドプローブは固形支持体に結合される。
図2に示すように、プローブがハイブリダイズしていないときは、報知分子の蛍光を消光するために該消光分子は報知分子に十分近接できるように少なくとも1つの一本鎖構造をとることができる。さらに図2に示すように、プローブが標的配列とハイブリダイズしたときは、プローブは、報知分子の蛍光を消光するために消光分子が報知分子に十分近接した位置に存在しない少なくとも1つの構造をとる。結果として、プローブが標的配列とハイブリダイズするときは報知分子の蛍光強度は増加する。
図2に示すように、異なるプローブを固形支持体に結合させ、サンプル中の異なる標的配列を同時に検出するために用いることができる。異なる蛍光波長をもつ報知分子を異なるプローブ上で用いることができ、したがって異なるプローブとのハイブリダイゼーションを別々に検出することができる。
オリゴヌクレオチド固定用の好ましい固形支持体の種類の例には、孔制御ガラス、ガラス板、ポリスチレン、アビジン被覆ポリスチレンビーズ、セルロース、ナイロン、アクリルアミドゲルおよび活性化デキストラン、CPG、ガラス板および高架橋ポリスチレンが含まれる。これらの固形支持体は、その化学的安定性、官能基付加が容易なことおよび輪郭の明瞭な表面領域のためにハイブリダイゼーション実験および診断実験に好ましい。孔制御ガラス(controlled pore glass(CPG)、500Å、1000Å)および非膨潤性高架橋ポリスチレン(1000Å)のような固形支持体は、オリゴヌクレオチド合成との適合性という観点から特に好ましい。
固形支持体とオリゴヌクレオチドの最初の3’ユニットとの間のリンカーの長さおよび化学的安定性は、効率の良い合成と支持体に結合したオリゴヌクレオチドのハイブリダイゼーションに重要な役割を果たす。リンカーアームは、自動合成時に高収量(>97%)を達成できるように十分に長くあるべきである。リンカーに必要な長さは用いられる個々の固形支持体によって異なる。例えば、固形支持体として高架橋ポリスチレンを用いる場合は、自動合成時に>97%の収量を達成するために一般に6原子のリンカーで十分である。CPGが固形支持体として用いられる場合、自動合成時に高収量(>97%)を達成するためにはリンカーアームは少なくとも長さが20原子であることが好ましい。
固形支持体に固定されたプローブのハイブリダイゼーションは、一般に、プローブが少なくとも30原子、より好ましくは少なくとも50原子固形支持体から離れていることを必要とする。この分離を達成するために、一般にリンカーは3’ヌクレオシドとリンカーとの間に配置されたスペーサーを含む。オリゴヌクレオチド合成のためには、リンカーアームは通常エステル結合によって3’ヌクレオシドの3’−OHに結合される。このエステル結合は塩基性試薬で切断され、固形支持体からオリゴヌクレオチドを遊離させることができる。
固形支持体にオリゴヌクレオチドプローブを結合させるために用いることができる種々のリンカーが当該分野で知られている。リンカーは、固形支持体に結合させたプローブと標的配列とのハイブリダイゼーションを顕著に干渉しないいずれの物質からも生成することができる。リンカーは、自動合成によってリンカーに容易に付加できるホモポリマーオリゴヌクレオチドから生成できる。また別に、官能基付加ポリエチレングリコールのようなポリマーもリンカーとして用いることができる。そのようなポリマーは、標的オリゴヌクレオチドとプローブとのハイブリダイゼーションに顕著に干渉しないのでホモポリマーオリゴヌクレオチドよりも好ましい。ポリエチレングリコールは、市販されていること、有機媒体および水性媒体の両方に可溶であること、官能基付加が容易であること、並びにオリゴヌクレオチド合成および合成後条件下で完全に安定であることから特に好ましい。
本発明のオリゴヌクレオチドプローブは、標的ポリヌクレオチドを検出するハイブリダイゼーションプローブとして用いることができる。したがって、本発明は、サンプル中の標的ポリヌクレオチドの存在を検出するハイブリダイゼーションアッセーに関する。本方法にしたがえば、本発明のオリゴヌクレオチドプローブは、ハイブリダイゼーションに都合のよい条件下で核酸サンプルと接触させられる。報知分子の蛍光シグナルはサンプルに接触させる前と後に測定される。プローブ上の報知分子は、標的配列とハイブリダイズしたときはより強い蛍光シグナルを示すので、サンプルとプローブを接触させた後の蛍光シグナルの増加は、サンプル中の標的配列とプローブとのハイブリダイゼーションを示唆し、したがってサンプル中の標的配列の存在が示される。さらに、プローブをサンプルと接触させた結果としての蛍光強度の変化を定量することによってサンプル中の標的配列の量を定量することができる。
本方法の一実施態様にしたがえば、ハイブリダイゼーションプローブは固形支持体に固定される。オリゴヌクレオチドプローブは、ハイブリダイゼーションに適した条件下で核酸サンプルと接触させられる。報知分子の蛍光シグナルはサンプルに接触させる前と後に測定される。プローブ上の報知分子は、標的配列とハイブリダイズしたときはより強い蛍光シグナルを示すので、サンプルとプローブを接触させた後の蛍光シグナルの増加は、サンプル中の標的配列とプローブとのハイブリダイゼーションを示唆する。固形支持体へのハイブリダイゼーションプローブの固定によって、プローブとハイブリダイズした標的配列を容易にサンプルから分離できる。以後の工程で、分離された標的配列を固形支持体から分離し、研究者の個々のニーズにしたがって当該分野で周知の方法によってさらに処理(例えば精製、増幅)することができる。
本発明のオリゴヌクレオチドプローブはまた、核酸増幅をモニターするプローブとして用いることができる。したがって、本発明は、増幅プライマーに対して3’側で標的配列とハイブリダイズできる本発明のオリゴヌクレオチドプローブを用いて核酸増幅をモニターする方法に関する。本方法にしたがえば、核酸増幅は、5’→3’ヌクレアーゼ活性をもつ核酸ポリメラーゼ、標的ポリヌクレオチドとハイブリダイズできるプライマー、およびプライマーに対して3’側で標的ポリヌクレオチドとハイブリダイズできる本発明のオリゴヌクレオチドプローブを用いて標的ポリヌクレオチドについて実施される。増幅中に、この核酸ポリメラーゼは、オリゴヌクレオチドプローブが標的配列とハイブリダイズしたとき該オリゴヌクレオチドプローブを消化し、したがって消光分子から報知分子を分離する。増幅が進行しているとき報知分子の蛍光がモニターされ、蛍光の発生は核酸の増幅に対応する。
核酸増幅をモニターする本発明のオリゴヌクレオチドプローブの使用によって従来の報知分子−消光分子対プローブの使用を越えるいくつかの利点が提供される。例えば、従来のプローブは、消光分子が報知分子の最小消光距離内に維持されるように報知分子と消光分子がプローブ上に配置される必要があった。しかしながら、消光分子が報知分子の最小消光距離内に存在するような構造をプローブがとることができるようにプローブをデザインしさえすればよいということが分かったので、はるかに様々なプローブが可能である。例えば、その5’および3’末端に報知分子と消光分子をもつ二重標識プローブをデザインすることができる。そのようなプローブは、報知分子または消光分子を内部ヌクレオチドに結合させたプローブよりもはるかに合成が容易である。末端ヌクレオチドに報知分子と消光分子を配置することによって、プローブのハイブリダイゼーション効率もまた強化される。
本出願で用いるように、“オリゴヌクレオチド”という用語は、天然または修飾モノマーまたは連合体(デオキシリボヌクレオシド、リボヌクレオシドなどを含む)の直線状オリゴマーで、モノマー対モノマー相互作用の規則的なパターン(例えばワトソン−クリック型塩基対形成など)によって標的ポリヌクレオチドと結合できるものを含む。通常モノマーはホスホジエステル結合またはその類似体によって連結され、サイズが数モノマー単位(例えば3−4)から数十モノマー単位のオリゴヌクレオチドを形成する。オリゴヌクレオチドが文字の配列(例えば“ATGCCTG”)で表現される場合は、ヌクレオチドは左から右に5’→3’の方向であり、さらに特に記載がなければ“A”はデオキシアデノシン、“C”はデオキシシチジン、“G”はデオキシグアノシン、“T”はデオキシチミジンを表すことは理解されよう。ホスホジエステル連結の類似体には、ホスホロチオエート、ホスホロジチオエート、ホスホルアニリデート、ホスホルアミデートなどが含まれる。一般に、本発明のオリゴヌクレオチドプローブはその5’末端に隣接して十分な数のホスホジエステル結合を有し、それによって用いられた5’→3’エクソヌクレアーゼ活性が効果的に結合したプローブを分解して報知分子と消光分子を分離させることができる。
本出願で用いられるように、“ヌクレオシド”には、コーンバーグとベーカー著の「DNA複製」(Kornberg & Baker,DNA Replication,第2版 Freeman刊、サンフランシスコ、1992)に記載されているように2’−デオキシおよび2’−ヒドロキシル型を含む天然のヌクレオシドが含まれる。ヌクレオシドに関して“類似体”という場合は、例えば文献(Scheit,ヌクレオチド類似体(Nucleotide Analogs)、John Wiley刊、ニューヨーク、(1980);Uhlman & Peyman,Chemical Reviews,90:543-584(1990)など)に記載された修飾塩基部分および/または修飾糖部分をもつ合成ヌクレオシドを含むが、ただしそれらが特異的なハイブリダイゼーションが可能であることを条件とする。そのような類似体には、結合特性を強化させ、縮退を減少させ、特性を強化させるようにデザインした合成ヌクレオシドが含まれる。
本発明のオリゴヌクレオチドプローブは多数の手段(例えば、Ozakiら、Nucleic Acids Research,20:5205-5214(1992);Agrawalら、Nucleic Acids Research,18:5419-5423(1990)など)によって合成できる。本発明のオリゴヌクレオチドプローブは、自動DNA合成装置(例えばApplied Biosystems,Inc.製、モデル392または394DNA/RNA合成装置(Foster City,カリフォルニア))で通常の化学操作(例えばホスホルアミダイト化学)を用いて例えば以下の文献に開示されたように都合よく合成できる(Beaucage & Iyer,Tetrahedron,48:2223-2311(1992);Molkoら、米国特許第4980460 号; Kosterら、米国特許第4725677号;Caruthersら、米国特許第4415732号;4458066号;4973679号など)。また別の化学操作(例えば非天然のバックボーン基(例えばホスホロチオエート、ホスホルアミデート)を生じるもの)もまた用いることができるが、生成されたオリゴヌクレオチドのハイブリダイゼーション効率および/または用いるエクソヌクレアーゼの切段効率に悪影響を及ぼさないことを条件とする。
好ましくは、オリゴヌクレオチドプローブの3’末端ヌクレオチドは封鎖するか、または核酸ポリメラーゼによる伸長を不可能にさせる。そのような封鎖は、連結部分によってオリゴヌクレオチドプローブの末端3’炭素に報知分子または消光分子を結合させることによって都合よく実施できる。
好ましくは、報知分子は、プローブの末端3’炭素または末端5’炭素に連結部分を介して結合させるために誘導した蛍光有機染料である。好ましくは、消光分子もまた有機染料であるが、これは、本発明の実施態様にしたがって蛍光性であってもなくてもよい。例えば、本発明の好ましい実施態様では消光分子は蛍光性である。一般に、消光分子が蛍光性であるにせよ、または非放射性衰退によって報知分子の転移エネルギーを単に遊離させるにせよ、消光分子の吸収バンドは実質的に報知分子の蛍光放出バンドと重なるべきである。励起した報知分子(しかし放射性エネルギーを遊離しない)のエネルギーを吸収する非蛍光性消光分子を本出願では色原体分子と呼ぶ。
個々のプローブについて適切な報知分子−消光分子対を選択するために極めて多くの手引が文献から入手できる。例を挙げれば以下の通りである:Clegg(上記に引用);Wuら(上記に引用);Pesceら編、蛍光分光学(Fluorescence Spectroscopy)(Marcel Dekker刊、ニューヨーク(1971));Whiteら、蛍光分析:実技(Fluorescence Analysis:A Practical Approach)(Marcel Dekker刊、ニューヨーク(1970))など。文献はまた、蛍光分子および色原体分子、並びに報知分子−消光分子対を選択するための関連するそれらの光学的特性の膨大なリストを提供する参考文献を含むが、これらは例えば以下のものである:Berlman,芳香族分子の蛍光スペクトルハンドブック(Handbook of Fluorescent Spectra of Aromatic Molecules)、第2版(Academic Press刊、ニューヨーク(1971)); Griffiths,有機分子の色と組成(colour & Constitution of Organic Molecules)(Academic Press刊、ニューヨーク(1971));Bishop編、インジケーター(Indicators)(Pergamon Press刊、オックスフォード(1972); Haugland,蛍光プローブと研究用化学物質ハンドブック(Handbook of Fluorescent Probes and Research Chemicals)(MolecularProbes刊、ユージーン(1992)); Pringsheim,蛍光と燐光(Fluorescence and Phosphorescence)(Interscience Publishers刊、ニューヨーク(1949))など。さらに、オリゴヌクレオチドに付加することができる一般的な反応基を介して共有結合によって結合させることができる報知分子および消光分子を誘導する様々な手引が文献にある。例を挙げれば以下のとおりである:Ullmanら、米国特許第3996345号; Khannaら、米国特許第4351760号など。
好ましくは、報知分子および消光分子はフルオレセインおよびローダミン染料から選ばれる。これらの染料およびオリゴヌクレオチドに結合させる適切な連結方法は多くの文献に記載されている。例えば以下の通りである:Khannaら(上記に引用);Marshall,Histochemical J.,7:299-303(1975); Menchenら、米国特許第5188934号;Menchenら、欧州特許出願公開公報第87310256.0号;Bergotら、国際特許出願PCT/US90/05565号。後者の4つの文献は参照により本明細書に含まれる。
多くの連結用部分並びに報知分子および消光分子をオリゴヌクレオチドの5’または3’末端に結合させる方法があるが、例を挙げれば以下の通りである:Eckstein編、オリゴヌクレオチドと類似体:実際的手技(Oligonucleotides and Analogues:A Practical Approach)(IRL Press 刊、オックスフォード(1991)); Zuckerman ら、Nucleic Acids Research,15:5305-5321(1987)(オリゴヌクレオチドの3’チオール基);Sharmaら、Nucleic Acids Research,19:3019(1991)(3’スルフヒドリル);Giustiら、PCR Methods and Applications,2:223-227(1993);Fungら、米国特許第4757141号(AminolinkTMII(Applied Biosystems(Foster City,CA)より市販)を介した5’ホスホアミノ基);Stabinsky,米国特許第4739044号(3’アミノアルキルホスホリル基); Agrawalら、Tetrahedron Letters,31:1543-1546(1990)(ホスホルアミデート連結による結合);Sproatら、Nucleic Acids Research,15:4837(1987)(5’メルカプト基);Nelsonら、Nucleic Acids Research,17:7187-7194(1989)(3’アミノ基)など。
好ましくは、合成中にオリゴヌクレオチドに結合させることができる市販の連結部分(例えばClontech Laboratories(パロアルト、カリフォルニア)から入手できる)が用いられる。
ローダミンおよびフルオレセイン染料はまた、ホスホルアミダイト部分とともに誘導した染料を用いて固相合成の終了時にオリゴヌクレオチドの5’ヒドロキシルに都合よく結合させられる(例えば、Hobbs,Jr.,米国特許第4997928 号; Wooら、米国特許第5231191号)。
これらの実施例で詳述する固有のプローブ、プローブ構築物および方法の工程は限定を意図するものではない。上記以外の本発明のさらなる目的および利点は、本発明の範囲を限定することを目的としない実施例から明らかになろう。
実施例
1.オリゴヌクレオチドプローブの合成
この実施例では表1に示すオリゴヌクレオチドの合成を説明する。リンカーアームヌクレオチド(“LAN”)のホスホルアミダイトはグレンリサーチ(Glen Research)から入手した。標準DNAホスホルアミダイト、6−カルボキシフルオレセイン(“6−FAM”)ホスホルアミダイト、6−カルボキシテトラメチルローダミンスクシンイミジルエステル(“TAMRANHSエステル”)、および3’封鎖ホスフェートを結合させるためのホスファリンク(PhosphalinkTM)はパーキン・エルマーのアプライドバイオシステムズ部門(Perkin-Elmer,Applied Biosystems Division)から入手した。オリゴヌクレオチド合成はモデル394DNA合成装置(Applied Biosystems)で実施した。プライマーおよび相補性オリゴヌクレオチドはオリゴピューリフィケーションカートリッジ(Oligo Purification Cartridges,Applied Biosystems)を用いて精製した。二重標識プローブは、5’末端の6−FAM−標識ホスホルアミダイト、オリゴヌクレオチド配列内のTの1つを置換したLANおよび3’末端のホスファリンクを用いて合成した。脱保護とエタノール沈澱に続いて、250mMの重曹緩衝液(pH9.0)で室温でLAN−含有オリゴヌクレオチドとTAMRANHSエステルを共役させた。未反応染料をPD−10セファデックスカラムに通して除去した。最後に、二重標識プローブを標準的プロトコルによって調製用HPLCで精製した。下記に表1の配列とLAN−TAMRA部分の位置を示すことによってプローブの名称を表示する。例えば、プローブA1−7は、5’末端から7位のヌクレオシドにLAN−TAMRAを有するA1配列をもつ。
高架橋ポリスチレン(1000Å)および孔制御ガラス(CPG)(500Å)の両方を固形支持体マトリックスとして用いる。スペーサー(化合物5)の官能基付加は表2に示す。スペーサーのポリスチレンおよびCPG支持体への結合、および該固形支持体のTAMRA染料による標識は表3および表4にそれぞれ示す。
表2は、CPGおよびポリスチレン支持体を誘導するために用いられるスペーサー(化合物5)の合成の反応模式図を示す。表2に示すように、DMF中のHOBT/HBTU/DIPEAの存在下でN−Fmoc−ε−アミノカプロン酸をDL−ホモセリンと反応させ(Knorrら、Tetrahedron Lett.,30:1927(1989))、65%の収量で化合物2を生じた。ピリジン中のDMAPの存在下で化合物2を塩化ジメトキシトリチルと反応させ、クロマトグラフィー後に72%の収量で化合物3を得た。DMF中のHOBT/HBTU/DIPEAの存在下で化合物3を極めて過剰のPEG−ジアミンで処理し(Buckmannら、Biotech.Appl.Biochem.,9:258(1987))、60%の収量でアミン4を得た。続いてアミン4をCH2Cl2中の無水コハク酸/Et3N/DMAPで処理してアミン4を90%収量でスクシネート5に変換した。さらに、このスクシネート5をさらに精製することなくポリスチレンおよびCPG支持体に表3および表4にそれぞれ示したように結合させた。
表3および表4に示したように、DMF中のHOBT/HBTU/DIPEAの存在下でスクシネート5をポリスチレンおよびCPG支持体と別々に反応させ、それぞれ官能基付加支持体6(5μmol/gローディング)および官能基付加支持体8(15μmol/gローディング)を提供した。支持体6および8をDMFに20%のピペリジンで処理することによって支持体結合スペーサーからFmocを除去した(Fieldsら、J.Peptide Res.35:161(1990))アミンを得、これをTAMRANHSエステルで処理してそれぞれTAMRA標識支持体7および9を得た。トリチル陽イオン分析でポリスチレンおよびCPG支持体は最終ローディングがそれぞれ4.8μmol/gおよび14μmol/gであることが分かった。
二重標識TaqmanプローブをTAMRA標識支持体7および9の両方、FastPhoramidite(ユーザーブリテン85号、Perkin Elmer Corporation 1994)並びにFAMホスホルアミダイト(ユーザーブリテン78号、Perkin Elmer Corporation 1994)を40ナノモルの規模で用いて合成した。65℃で3時間、MeOH:t−BuNH2:H2O(1:1:2)で処理して支持体結合オリゴヌクレオチドを脱保護した(Wooら、米国特許5231191号)。液体を除去し、プローブを含む支持体をH2O:MeOH(3:1)およびMeOHで洗浄した。続いて支持体を真空下で乾燥させハイブリダイゼーションアッセーに用いた。
化合物2:N,N−ジイソプロピルエチルアミン(1.1g、1.48ml、8.52mmol)、1−ヒドロキシベンゾトリアゾル(420mg、3.1mmol)および(2−(1H−ベンゾトリアゾル−1−イル)1,1,3,3−テトラメチルウロニウムヘキサフルオロホスフェート(1.17g、3.1mmol)をDMF(30ml)中のNfmoc−ε−アミノカプロン酸(1g、2.84mmol)の攪拌溶液に室温で添加した。15分後、DL−ホモセリン(1.35g、11.36mmol)を反応混合物に加えた。3時間後、減圧下でDMFを除去した。残留物をCHCl3(100ml)に溶解し、5%塩酸(2×50ml)で洗浄した。有機層をMgSO4上で乾燥させ、蒸発させて濃厚な油を得てエーテルで粉末化し無色の固形物を得た(840mg、65%)。生成物を高圧下に24時間放置し、さらに精製することなく次の工程に用いた。
化合物3:塩化4,4’−ジメトキシトリチル(484mg、1.43mmol)
および4−ジメチアミノピリジン(25mg、0.2mmol)をピリジン(15ml)中の化合物2(500mg、1.1mmol)の攪拌溶液に窒素雰囲気下で室温で加えた。14時間後、ピリジンを除去し、残留物をCHCl3(70ml)に溶解した。有機層を5%クエン酸(1×50ml)、H2O(1×50ml)および飽和ブライン(1×50ml)で抽出した。有機層をMgSO4上で乾燥させ、蒸発させて黄色の泡沫を得た。生成物をCHCl3−MeOH勾配(0−10%MeOH)で溶出させながらシリカゲルカラムで精製した。適切な分画を合わせて、蒸発させ無色泡沫として化合物3を得た(600mg、72%)。
化合物4:ポリ(エチレングリコール)ビス(2−アミノエチルエーテル)(3.16g、5.3mmol)、N,N−ジイソプロピルエチレンアミン(205mg、0.27ml、1.59mmol)、1−ヒドロキシベンゾトリアゾル(78mg、0.58mmol)および(2−(1H−ベンゾトリアゾル−1−イル)−1,1,3,3,−テトラメチルウノニウムヘキサフルオロホスフェート(220mg、0.58mmol)を、DMF(10ml)中の化合物3(400mg、0.53mmol)
の攪拌溶液に室温で添加した。減圧下でDMFを除去し、残留物をCHCl3(70ml)に溶解し、有機層をH2O(1×50ml)および飽和ブライン(2×50ml)で洗浄した。有機層をMgSO4上で乾燥させ、蒸発させて濃厚な油を得た。化合物4をCHCl3−MeOH勾配(5−15%MeOH)で溶出させながらシリカゲルカラムで精製し無色ガラス(423mg、60%)とした。
TAMRA染料によるポリスチレン支持体の誘導体形成:DMF(10ml)
中の化合物5(17mg、12μmol)、1−ヒドロキシベンゾトリアゾル(1.8mg、12μmol)、(2−(1H−ベンゾトリアゾル−1−イル)−1,1,3,3−テトラメチルウオニウムヘキサフルオロホスフェート(4.8mg、12μmol)、N,N−ジイソプロピルエチルアミン(6μl、30μmol)で高架橋ポリスチレン(1000Å、10μmol/gアミンローディング、1g、10μmol)を室温で4時間リストアクションシェーカーで処理した。この支持体をDMF(3×10ml)、CH3CN(2×10ml)およびCH2Cl2(1×10ml)で洗浄し、強真空下で一晩乾燥させた。ニンヒドリンアッセーによって1μmol/gのアミンが残っているのが分かった。トリチル陽イオンアッセーは化合物5の5μmol/gローディングを示した。この支持体をTHF中の無水酢酸/ルチジン(10%溶液、5ml)およびTHF中の1−メチルイミダゾル(16%溶液、5ml)で2時間室温で処理した。支持体をCH3CN(3×10ml)およびCH2Cl2(1×10ml)で洗浄した。支持体をDMF中の20%ピペリジン(3×10ml)で処理しFmoc保護基を除去した。Fmoc基の除去は302nmで溶液のUVを測定することによってモニターした。支持体をDMF(3×10ml)で洗浄し、続いてTAMRANHSエステル(15mg、27μmol)およびDMF(10ml)中のEt3N(50μmol)で42時間シェーカー上で処理した。支持体をDMF(3×10ml)、CH3CN(2×10ml)およびCH2Cl2(1×10ml)で洗浄し、強真空下で24時間乾燥させた。ニンヒドリンテストによって0.5μmol/g未満のアミンが残っているのが分かった。支持体をTHF中の無水酢酸/ルチジン(10%溶液、5ml)およびTHF中の1−メチルイミダゾル(16%溶液、5ml)で1時間室温で処理し、続いてCH3CN(3×10ml)およびCH2Cl2(2×10ml)で洗浄して強真空下で24時間乾燥させた。トリチル陽イオンアッセーは4.8μmol/gの最終ローディングを示した。
FAMおよびTAMRA二重標識プローブの合成:TAMRA標識支持体7および9、DNAFastPhosphoramidite およびFAMを40nmol規模で用いて二重染料標識プローブを合成した。合成終了後、プローブを含む支持体を4mlのガラスバイアルに移し、MeOH:t−BuNH2:H2O(1:1:2)の混合物で3時間65℃で処理した。注射筒で液体を除去し、支持体をH2O:MeOH(3:1)およびMeOHで洗浄した。真空下で支持体を乾燥させハイブリダイゼーションアッセーに用いた。
ヒトβ−アクチン遺伝子のエクソン3の295塩基対セグメント(S.Nakajima-Iijima(Proc.Natl.Acad.Sci.USA 82:6133-6137(1985))が開示したヌクレオチド2141−2435)は、10mMトリス−HCl(pH8.3)、50mMKCl、4mMMgCl2、300mMのプライマーAFP(配列番号:7)、300nMのプライマービオチン−ARP(5’末端にビオチンを結合させた配列番号:8)、200μMdATP、200μMdCTP、200μMdGTP、200μMdTTPおよび1.25単位のAmpliTaq(Perkin-Elmer)を含む50μlの反応物を用いて増幅できる。反応は20ngのヒトゲノムDNAの存在下(+鋳型)または非存在下(−鋳型)で実施される。
50℃(2分);95℃(10分);さらに95℃(20秒)続いて60℃(1分)の40サイクルという温度循環の後、各サンプルに200μlのハイブリダイゼーション緩衝液(5×SSC、8%(v/v)ギ酸アミド、8%(v/v)トリトンX−100)を添加して希釈する。生じたサンプルをストレプトアビジン被覆96穴(ウェル)のマイクロタイタープレート(Xenopore Corp.,サッドルブルック、ニュージャージー)に移し、増幅β−アクチンDNAセグメントを捕捉するために37℃で30分保温した。続いて各ウェルを350μlの燐酸緩衝食塩水/0.05%トゥイーン−20で洗浄した。一切の非ビオチン化DNAを100μlの0.1MNaOH/1mMEDTAを添加することによって除去し、室温で5分保温し、350μlの燐酸緩衝食塩水/0.05%トゥイーン−20で洗浄する。続いて、プローブA1−26(配列番号:9、ヌクレオチド1−26(A1−26)、報知分子FAMおよび消光分子TAMRAで標識)を100nM含むハイブリダイゼーション緩衝液の50μlを加え、37℃で30分保温する。
続いて、パーキン・エルマータックマン(Perkin-Elmer TaqMan)LS−50Bシステムを用いて518nmおよび582nmで蛍光を測定する。続いて実施例5で述べるようにΔRQを算出する。ΔRQの大きさはA1−26プローブのハイブリダイゼーションのレベルを示し、したがって各ウェルに捕捉された増幅β−アクチンDNAセグメント量の大きさである。
3通りのプローブ/固形支持体組み合わせを調べた:A1−PS:ポリスチレン支持体に結合させたA1(配列番号:9);A1−CPG:ガラス支持体に結合させたA1(配列番号:9);およびG1−PS:ポリスチレン支持体に結合させたG1(配列番号:13)。
3つのプローブは全て当該配列の5’末端にFAMが結合され、TAMRAは3’末端に結合されている。50μlの1×PCR緩衝液(10mMトリス−HCl(pH8.3)、50mMKCl、3.5mMMgCl2)中に各プローブ/固形支持体を懸濁させることによって鋳型無し反応を調製した。鋳型+反応のためには、A1−PSおよびA1−CPGを50μlの1×PCR緩衝液+1μMのA1Cに懸濁し、G1−PSを50μlの1×PCR緩衝液+1μMのG1Cに懸濁した。
反応物を95℃で1分保温し、続いて室温まで徐冷した。各懸濁物の一部を顕微鏡スライドに載せた。各サンプルを488nm光で励起し、518nmまたは583干渉フィルターのいずれかを用いて蛍光像をCCDアレー上で捕捉した。
この像の分析は、518nm像の最大ピクセル値を見つけ、続いて同じピクセルについての583nm値を見つけることによって実施した。緩衝液で得られたバックグラウンドの読みを差し引くことによってピクセル値を修正した。表5は表示したプローブの蛍光測定値の結果を示す。
全てのPCR増幅はパーキン・エルマーサーモサイクラー9600で実施し、10mMトリス−HCl(pH8.3)、50mMKCl、200μMdATP、200μMdCTP、200μMdGTP、400μMdUTP、0.5単位のAmpEraseTMウラシルN−グリコリアーゼ(Perkin-Elmer)および1.25単位のAmpliTaqTM(Perkin-Elmer)を含む50μl反応物を用いた。ヒトβ−アクチン遺伝子のエクソン3の295塩基対セグメント(S.Nakajima-Iijima(Proc.Natl.Acad.Sci.USA 82:6133-6137(1985))が開示したヌクレオチド2141−2435)を以下に挙げたAFPおよびARPプライマーを用いて増幅した。増幅反応物は、4mMMgCl2、20ngヒトゲノムDNA、50nMA1またはA3プローブおよび各プライマー300nMを含んでいた。温度処理は以下の通りであった:50℃(2分);95℃(10分);95℃(20秒)、60℃(1分)の40サイクルおよび72℃での保持。515塩基対セグメントは、ベクターpUC119のSmaI部位に挿入されたλDNAのセグメント(ヌクレオチド32、220−32、747)から成るプラスミドで増幅した。これらの反応物は3.5mMMgCl2、1ngのプラスミドDNA、50nMのP2またはP5プローブ、200nMのプライマーF119および200nMのプライマーR119を含んでいた。温度処理は以下の通り:5℃(2分);95℃(10分):95℃(20秒)、57℃(1分)の25サイクル;および72℃での保持。
各増幅反応物について、40μlを96ウェルの白色マイクロタイタープレート(Perkin-Elmer)の個々のウェルに移した。蛍光はパーキン・エルマータックマン(登録商標)LS−50Bシステムで測定したが、このシステムは、プレート読み取り装置部、485nm励起フィルターおよび515nm発光フィルターをもつルミネッセンス分光計から成る。励起は、5nmのスリット幅を用いて488nmで実施した。発光は、6−FAM(報知分子、またはRバルブ)については518nmで、TAMRA(消光分子またはQバルブ)については582nmで10nmのスリット幅を用いて測定した。PCR中の切断による報知分子発光の増加を求めるために、3つの標準化を未処理発光データに用いた。第一に、緩衝液ブランクの発光強度を各波長について差し引いた。第二に、報知分子の発光強度を消光分子の発光強度で割って、各反応試験管についてRQ比を出した。
これによって、個々のウェルについてのプローブ濃度の変動と蛍光測定値の変動が標準化される。最後に、鋳型を含まないコントロールのRQ値(RQ-)を鋳型を含む完全な反応物のRQ値(RQ+)から差し引いてΔRQを算出する。
前述した本発明の好ましい実施態様は実例と説明のために提供し、開示した厳密な形態に限定することを目的とするものではない。当業者には多くの修飾および変形が明らかであろう。本発明の範囲は以下の請求の範囲およびその同等物によって範囲が定まる。
(2) 配列番号1:
(i) 配列の特徴:
(A) 配列の長さ: 24 ヌクレオチド
(B) 配列の型: 核酸
(C) 鎖の数: 一本鎖
(D) トポロジー: 直鎖状
(xi) 配列:配列番号:1:
ACCCACAGGA ACTGATCACC ACTC 24
(2) 配列番号2:
(i) 配列の特徴:
(A) 配列の長さ: 26 ヌクレオチド
(B) 配列の型: 核酸
(C) 鎖の数: 一本鎖
(D) トポロジー: 直鎖状
(xi) 配列:配列番号:2:
ATGTCGCGTT CCGGCTGACG TTCTGC 26
(2) 配列番号3:
(i) 配列の特徴:
(A) 配列の長さ: 27 ヌクレオチド
(B) 配列の型: 核酸
(C) 鎖の数: 一本鎖
(D) トポロジー: 直鎖状
(xi) 配列:配列番号:3:
TCGCATTACT GATCGTTGCC AACCAGT 27
(2) 配列番号4:
(i) 配列の特徴:
(A) 配列の長さ: 31 ヌクレオチド
(B) 配列の型: 核酸
(C) 鎖の数: 一本鎖
(D) トポロジー: 直鎖状
(xi) 配列:配列番号:4:
GTACTGGTTG GCAACGATCA GTAATGCGAT G 31
(2) 配列番号5:
(i) 配列の特徴:
(A) 配列の長さ: 28 ヌクレオチド
(B) 配列の型: 核酸
(C) 鎖の数: 一本鎖
(D) トポロジー: 直鎖状
(xi) 配列:配列番号:5:
CGGATTTGCT GGTATCTATG ACAAGGAT 28
(2) 配列番号6:
(i) 配列の特徴:
(A) 配列の長さ: 31 ヌクレオチド
(B) 配列の型: 核酸
(C) 鎖の数: 一本鎖
(D) トポロジー: 直鎖状
(xi) 配列:配列番号:6:
TTCATCCTTG TCATAGATAC CAGCAAATCC G 31
(2) 配列番号7:
(i) 配列の特徴:
(A) 配列の長さ: 25 ヌクレオチド
(B) 配列の型: 核酸
(C) 鎖の数: 一本鎖
(D) トポロジー: 直鎖状
(xi) 配列:配列番号:7:
TCACCCACAC TGTGCCCATC TACGA 25
(2) 配列番号8:
(i) 配列の特徴:
(A) 配列の長さ: 25 ヌクレオチド
(B) 配列の型: 核酸
(C) 鎖の数: 一本鎖
(D) トポロジー: 直鎖状
(xi) 配列:配列番号:8:
CAGCGGAACC GCTCATTGCC AATGG 25
(2) 配列番号9:
(i) 配列の特徴:
(A) 配列の長さ: 26 ヌクレオチド
(B) 配列の型: 核酸
(C) 鎖の数: 一本鎖
(D) トポロジー: 直鎖状
(xi) 配列:配列番号:9:
ATGCCCTCCC CCATGCCATC CTGCGT 26
(2) 配列番号10:
(i) 配列の特徴:
(A) 配列の長さ: 30 ヌクレオチド
(B) 配列の型: 核酸
(C) 鎖の数: 一本鎖
(D) トポロジー: 直鎖状
(xi) 配列:配列番号:10:
AGACGCAGGA TGGCATGGGG GAGGGCATAC 30
(2) 配列番号11:
(i) 配列の特徴:
(A) 配列の長さ: 24 ヌクレオチド
(B) 配列の型: 核酸
(C) 鎖の数: 一本鎖
(D) トポロジー: 直鎖状
(xi) 配列:配列番号:11:
CGCCCTGGAC TTCGAGCAAG AGAT 24
(2) 配列番号12:
(i) 配列の特徴:
(A) 配列の長さ: 28 ヌクレオチド
(B) 配列の型: 核酸
(C) 鎖の数: 一本鎖
(D) トポロジー: 直鎖状
(xi) 配列:配列番号:12:
CCATCTCTTG CTCGAAGTCC AGGGCGAC 28
(2) 配列番号13:
(i) 配列の特徴:
(A) 配列の長さ: 21 ヌクレオチド
(B) 配列の型: 核酸
(C) 鎖の数: 一本鎖
(D) トポロジー: 直鎖状
(xi) 配列:配列番号:13:
CAAGCTTCCC GTTCTCAGCC T 21
(2) 配列番号14:
(i) 配列の特徴:
(A) 配列の長さ: 30 ヌクレオチド
(B) 配列の型: 核酸
(C) 鎖の数: 一本鎖
(D) トポロジー: 直鎖状
(xi) 配列:配列番号:14:
ACCGTCAAGG CTGAGAACGG GAAGCTTGTC 30
Claims (1)
- 自分自身とハイブリダイズしてヘアピン構造を形成しないオリゴヌクレオチド配列、当該オリゴヌクレオチド配列に結合された蛍光報知分子及び当該オリゴヌクレオチド配列に結合された当該蛍光報知分子の蛍光を消光できる消光分子を含むオリゴヌクレオチドプローブであって、
当該オリゴヌクレオチド配列は、ハイブリダイズしていないときは少なくとも一本鎖構造で存在することができ、この場合、当該消光分子は当該報知分子の蛍光を消光し、
当該オリゴヌクレオチド配列は、標的ポリヌクレオチドとハイブリダイズしているときは少なくとも1つの構造で存在することができ、この場合、当該報知分子の蛍光は消去されず、
当該オリゴヌクレオチド配列が当該標的ポリヌクレオチドとハイブリダイズしているときに最大発光の当該報知分子の蛍光強度は、当該オリゴヌクレオチド配列が当該標的ポリヌクレオチドとハイブリダイズしていないときに最大発光の当該報知分子の蛍光強度よりも少なくとも6倍強いオリゴヌクレオチドプローブ。
Applications Claiming Priority (1)
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US08/340,558 US5538848A (en) | 1994-11-16 | 1994-11-16 | Method for detecting nucleic acid amplification using self-quenching fluorescence probe |
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JP2002260129A Division JP2003144198A (ja) | 1994-11-16 | 2002-09-05 | 自己消光性蛍光プローブと方法 |
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JP51632196A Expired - Lifetime JP4131749B2 (ja) | 1994-11-16 | 1995-11-15 | 自己消光性蛍光プローブと方法 |
JP2002260129A Pending JP2003144198A (ja) | 1994-11-16 | 2002-09-05 | 自己消光性蛍光プローブと方法 |
JP2005075576A Pending JP2005176858A (ja) | 1994-11-16 | 2005-03-16 | 自己消光性蛍光プローブと方法 |
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JP51632196A Expired - Lifetime JP4131749B2 (ja) | 1994-11-16 | 1995-11-15 | 自己消光性蛍光プローブと方法 |
JP2002260129A Pending JP2003144198A (ja) | 1994-11-16 | 2002-09-05 | 自己消光性蛍光プローブと方法 |
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US (5) | US5538848A (ja) |
EP (2) | EP0972848A3 (ja) |
JP (3) | JP4131749B2 (ja) |
AT (1) | ATE198775T1 (ja) |
CA (1) | CA2201756C (ja) |
DE (1) | DE69519940T2 (ja) |
WO (1) | WO1996015270A1 (ja) |
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- 1995-11-15 US US08/559,405 patent/US5723591A/en not_active Expired - Lifetime
- 1995-11-15 EP EP95941402A patent/EP0792374B1/en not_active Expired - Lifetime
- 1995-11-15 CA CA002201756A patent/CA2201756C/en not_active Expired - Fee Related
-
1998
- 1998-12-07 US US09/207,170 patent/US6030787A/en not_active Expired - Lifetime
-
1999
- 1999-11-08 US US09/436,454 patent/US6258569B1/en not_active Expired - Lifetime
-
2002
- 2002-09-05 JP JP2002260129A patent/JP2003144198A/ja active Pending
-
2005
- 2005-03-16 JP JP2005075576A patent/JP2005176858A/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
US5723591A (en) | 1998-03-03 |
EP0792374A1 (en) | 1997-09-03 |
EP0792374B1 (en) | 2001-01-17 |
AU4283696A (en) | 1996-06-06 |
JP4131749B2 (ja) | 2008-08-13 |
ATE198775T1 (de) | 2001-02-15 |
US6258569B1 (en) | 2001-07-10 |
JP2003144198A (ja) | 2003-05-20 |
US5538848A (en) | 1996-07-23 |
US5876930A (en) | 1999-03-02 |
EP0972848A3 (en) | 2000-10-04 |
CA2201756A1 (en) | 1996-05-23 |
CA2201756C (en) | 2005-02-08 |
DE69519940D1 (de) | 2001-02-22 |
EP0972848A2 (en) | 2000-01-19 |
JPH10510982A (ja) | 1998-10-27 |
WO1996015270A1 (en) | 1996-05-23 |
US6030787A (en) | 2000-02-29 |
DE69519940T2 (de) | 2001-05-23 |
AU695561B2 (en) | 1998-08-13 |
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