JP7383674B2 - 非天然ヌクレオチドの取り込みによるインビトロの核酸の部位特異的な酵素標識のための方法 - Google Patents
非天然ヌクレオチドの取り込みによるインビトロの核酸の部位特異的な酵素標識のための方法 Download PDFInfo
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- JP7383674B2 JP7383674B2 JP2021147954A JP2021147954A JP7383674B2 JP 7383674 B2 JP7383674 B2 JP 7383674B2 JP 2021147954 A JP2021147954 A JP 2021147954A JP 2021147954 A JP2021147954 A JP 2021147954A JP 7383674 B2 JP7383674 B2 JP 7383674B2
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- 239000011535 reaction buffer Substances 0.000 description 1
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- 108091092562 ribozyme Proteins 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 239000004055 small Interfering RNA Substances 0.000 description 1
- 108091029842 small nuclear ribonucleic acid Proteins 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- IBKZNJXGCYVTBZ-IDBHZBAZSA-M sodium;1-[3-[2-[5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]ethyldisulfanyl]propanoyloxy]-2,5-dioxopyrrolidine-3-sulfonate Chemical compound [Na+].O=C1C(S(=O)(=O)[O-])CC(=O)N1OC(=O)CCSSCCNC(=O)CCCC[C@H]1[C@H]2NC(=O)N[C@H]2CS1 IBKZNJXGCYVTBZ-IDBHZBAZSA-M 0.000 description 1
- 229940063673 spermidine Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- ABZLKHKQJHEPAX-UHFFFAOYSA-N tetramethylrhodamine Chemical compound C=12C=CC(N(C)C)=CC2=[O+]C2=CC(N(C)C)=CC=C2C=1C1=CC=CC=C1C([O-])=O ABZLKHKQJHEPAX-UHFFFAOYSA-N 0.000 description 1
- MPLHNVLQVRSVEE-UHFFFAOYSA-N texas red Chemical compound [O-]S(=O)(=O)C1=CC(S(Cl)(=O)=O)=CC=C1C(C1=CC=2CCCN3CCCC(C=23)=C1O1)=C2C1=C(CCC1)C3=[N+]1CCCC3=C2 MPLHNVLQVRSVEE-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- WVLBCYQITXONBZ-UHFFFAOYSA-N trimethyl phosphate Chemical compound COP(=O)(OC)OC WVLBCYQITXONBZ-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BZVJOYBTLHNRDW-UHFFFAOYSA-N triphenylmethanamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(N)C1=CC=CC=C1 BZVJOYBTLHNRDW-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 241001515965 unidentified phage Species 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 150000008136 β-glycosides Chemical class 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/24—Heterocyclic radicals containing oxygen or sulfur as ring hetero atom
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
- C12N15/102—Mutagenizing nucleic acids
- C12N15/1024—In vivo mutagenesis using high mutation rate "mutator" host strains by inserting genetic material, e.g. encoding an error prone polymerase, disrupting a gene for mismatch repair
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
- C12N9/22—Ribonucleases RNAses, DNAses
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/26—Preparation of nitrogen-containing carbohydrates
- C12P19/28—N-glycosides
- C12P19/30—Nucleotides
- C12P19/34—Polynucleotides, e.g. nucleic acids, oligoribonucleotides
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- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6813—Hybridisation assays
- C12Q1/6832—Enhancement of hybridisation reaction
Description
本発明は国立衛生研究所によって与えられた認可番号GM060005下で政府の支援をうけて作られた。米国政府は本発明に一定の権利を有している。
本出願は2013年8月8日に出願された米国仮出願第61/863,649号の利益を主張し、該文献は参照によって全体として組み込まれる。
α6基の三リン酸塩を、Ludwig, J. および Eckstein, F. Rapidと、2-クロロ-4H-1,3,2-ベンゾジオキサホスホリン-4-オンを用いるヌクレオシド5’-0-(1-チオ三リン酸塩),5’-三リン酸塩、および2’,3’-シクロホスホロトエートの効率的な合成に従って、以前に報告されたヌクレオシド(Kubelka, T. , Slavetinska, L., Eigner, V. and Hocek, M. Synthesis of 2,6-disubstituted pyridin-3-yl C-2’-deoxyribonucleosides through chemoselective transformations of bromo-chloropyridine C-nucleosides. Org. Biomol. Chem., 11, 4702-4718)から調製した。他のすべての三リン酸塩の純度はMALDI-TOFとUV-VISによって確認された。TaqとOneTaqのDNAポリメラーゼをNew England Biolabs(Ipswich、MA)から購入した。デオキシリボヌクレオチド三リン酸の混合物をFermentas(Glen Burnie, MD)から購入した。SYBR Green I核酸ゲル染色(10,000×)をLife Technologies(Carlsbad、CA)から購入した。1-5回のスクリーニングに用いられるDNA鋳型、D8(Malyshev, D.A., Dhami, K., Quach, H.T., Lavergne, T. , Ordoukhanian, P., Torkamani, A. and Romesberg, F.E. Efficient and sequence-independent replication of DNA containing a third base pair establishes a functional six-letter genetic alphabet. Proc. Natl. Acad. Sci. USA, 109, 12005-12010)と、他のすべての増幅に使用されるD6(Malyshev, D.A., Seo, Y.J., Ordoukhanian, P. and Romesberg, F.E. PCR with an expanded genetic alphabet. J. Am. Chem. Soc., 131, 14620-14621)の合成は先に記載された。サンガー法シーケンシングは以前に記載された通りに実行された(Malyshev, D.A., Dhami, K., Quach, H.T., Lavergne, T., Ordoukhanian, P., Torkamani, A. and Romesberg, F.E. Efficient and sequence-independent replication of DNA containing a third base pair establishes a functional six-letter genetic alphabet. Proc. Natl. Acad. Sci. USA, 109, 12005-12010)。生のサンガー法シーケンシングの痕跡を用いて非天然の塩基対の保持パーセントを決定し、これを記載された通りに倍加当たりの忠実度に変換した(Malyshev, D.A., Dhami, K., Quach, H.T., Lavergne, T. , Ordoukhanian, P., Torkamani, A. and Romesberg, F.E. Efficient and sequence-independent replication of DNA containing a third base pair establishes a functional six-letter genetic alphabet. Proc. Natl. Acad. Sci. USA, 109, 12005-12010; Malyshev, D.A., Seo, Y.J., Ordoukhanian, P. and Romesberg, F.E. PCR with an expanded genetic alphabet. J. Am. Chem. Soc., 131, 14620-14621)。
プロトンスポンジ(1.3等量)と遊離ヌクレオシド誘導体(1.0等量)を、乾燥したトリメチルホスフェート(40等量)に溶かし、窒素雰囲気下で-15°Cに冷やした。新鮮に蒸留したPOCl3(1.3等量)を液滴で加え、結果として生じた混合物を2時間-10°Cで撹拌した。トリブチルアミン(6.0等量)と、ジメチルホルムアミド(0.5M)中のトリブチルアンモニウムピロリン酸塩(5.0等量)の溶液を加えた。30分にわたって反応を0°Cまでゆっくりと温め、その後、0.5Mの水性のEt3NH2CO3(TEAB)pH7.5(2容積等量)を加えてクエンチした。その混合物をH2Oで2倍に希釈し、生成物を0~1.2MのTEABの溶出勾配でDEAE Sephadex カラム(GE Healthcare)上で分離し、蒸発させ、H2O(3×)で共蒸留した。逆相(C18)HPLC(0.1MのTEAB中0-35%のCH3CN、pH7.5)によるさらなる精製を行った(10%-31%の収率)。
31P NMR (162 MHz, D2O)oe-10.8 (d,J= 19.8 Hz, y-P), -11.5 (d,J= 20.1 Hz, a-P), -23.3 (t,J= 20.1 Hz, f3-P).MS (MALDI-TOF-, マトリックス: 9-アミノアクリジン) (m/z):[M-H]- calcd for C13H17NO12P3S2, 536.3, found, 536.1
HRMS (ESI+) m/z calcd for C28H25FNO5S2 (M+H+) 538.1153, found 538.1155.
材料。TaqとOneTaqのDNAポリメラーゼをNew England Biolabs(Ipswich、MA)から購入した。dNTPの混合物をFermentas(Glen Burnie, MD)から購入した。SYBR Green I核酸ゲル染色(10,000×)をLife Technologies(Carlsbad、CA)から購入した。
中心に位置したdTPT3PA-dNaMあるいはd5SICSPA-dNaMを含む134量体のDNAが合成された。DNA鋳型は表9に記載される条件下でPCRにより増幅された。完了後、NaOH(1M、12.5μL)を、0.2Mの最終濃度になるまでPCRサンプルに直接加えて、室温で5時間培養した。NaOAc(3M、pH5.5、7.5μL)と200μLの冷たいエタノールの追加後、サンプルを混合し、氷の上で夜通しインキュベートし、DNAを4°Cで30分間10,000rfuで遠心分離によって沈殿させた。上清を取り除き、ペレット剤は80%のエタノールで注意深く洗浄した。サンプルを、50μLのアニーリング緩衝液(50mMのNaリン酸塩、pH7.5、100mMのNaCl、1mMのEDTA)中で再懸濁し、95°Cに加熱し、30分かけて室温まで冷やした。アニーリング緩衝液(40mM、50μL)中のNHS-PEG4-ビオチン(Thermo Scientific)溶液をDNAサンプルと混ぜ、室温で夜通しインキュベートした。サンプルを回転カラム(DNA Clean and Concentrator-5(Zymo Research))によって精製し、10μLの溶出緩衝液中で溶出させた。サンプル(5μL)の半分をアニーリング緩衝液中の1μgのストレプトアビジン(Promega)と混ぜ、37°Cで30分間インキュベートし、5x非変性添加液(Qiagen)と混ぜ、6%の非変性PAGE上に負荷した。残りの半分を5xの非変性添加液と混ぜ、対照としてゲルに直接負荷した。30分間110Vでゲルを泳動させた後に、ゲルを30分間1x Sybr Gold Nucleic Acid Stain(Life Technologies)中に浸漬させ、520DF30フィルタ(Bio-Rad)を装備したMolecular Imager Gel Doc XR+を使用して視覚化した。記載される標識化戦略の図が以下に記載される。
dTPT3およびdNaM、あるいはそのアナログまたは誘導体によって形成された非天然の塩基対の転写を特徴づけるために(誘導体はリンカー部分を含む)、リボヌクレオチドとデオキシリボヌクレオチドを合成し、対応する三リン酸塩またはデオキシホスホラミダイトに変換され、自動式DNA合成を使用してデオキシホスホラミダイトをDNA鋳型に取り込む。転写実験は100nMのDNA基質、1xTakara緩衝液(40mM Tris-HCl、pH8.0、8mMのMgCl2、2mMのスペルミジン)、DEPCで処理された、かつヌクレアーゼを含まない滅菌水(Fisher)、T7ポリメラーゼ(50単位)、20μMのそれぞれの天然のNTP、α-32P-ATP(2.5μCi、MP Biomedicals)、および、5μMのTPT3TP、あるいは5μMのNamTPで行われる。37°Cで2時間のインキュベーション後、10μLのゲル負荷溶液を加えて反応をクエンチし(10Mの尿素、0.05%のブロモフェノールブルー)、反応混合物を20%ポリアクリルアミド-7M尿素ゲルに載せ、電気泳動にかけて、ホスフォイメージング(phosphorimaging)によって分析する。時間関数として形成された完全長の生成物の量を測定すること(低い変換割合で)によって転写効率を調べる。
UV溶解実験はCary300Bio UV可視の分光光度計を使用して実行される。サンプル(非天然の塩基対、10mMのPIPES緩衝液、pH7.0、100mMのNaCl、10mMのMgCl2を含む3μLのオリゴヌクレオチド)の吸光度は、1分当たり0.5°Cの加熱速度で21°Cから80°Cまで260nmでモニタリングされる。融解温度はCary Win UV熱アプリケーションソフトウェアを使用して、誘導法によって決定される。
非天然の核酸を含むオリゴヌクレオチドライブラリーが生成される。ライブラリのサンプルは、標的分子(例えばタンパク質)との連続的な結合およびそれからの溶出にさらされる。結合核酸のプールはPCRによって増幅され、標的分子と結合するために再度の選択にさらされる。この選別プロセスは数回繰り返される。最後の数回の選択時に選択圧を増加させるために、標的分子の濃縮および/またはインキュベーション時間を減らす。生き残った核酸を潜在的なアプタマーとして配列決定される。潜在的なアプタマーの結合親和性はフローサイトメトリーを使用して決定される。
14μLのDMSO中のDNA溶液(0.2pmol)に、1μLのアジド-PEG(3+3)-S-S-ビオチン(H2O中の20mM)を加え、その後、2μLのリガンド(BimC4A)3(H2O中の4mM)、1μLのアスコルビン酸ナトリウム(H2O中の100mM)、および1μLのPBS緩衝液(5×)を加え、その後、その混合物をボルテックスし、最後の成分として、1μLの新鮮に調製したCuSO4溶液(H2O中の4mM)を加えた。その溶液を37°Cで2時間振り、その後、結果として生じる生成物DNAを精製した(DNA Clean & Concentrator-5 kit, Zymo Research Corp.)。精製されたサンプルを用いてゲル移動度アッセイに直接使用された(以下を参照)。
酵素合成後の標識について、遊離アミノ基を含むdsDNAを、リン酸標識緩衝液(50mMのリン酸ナトリウム、pH7.5、150mMのNaCl、1mMのEDTA)中で、室温で1時間10mMのEZーLinkスルフォ-NHS-SS-ビオチン、またはEZ-LinkNHS-PEG4-ビオチン(Thermo Scientific)を用いてインキュベートし、その後、Qiagen PCR精製キットを使用して精製した。dTPT3PAまたはd5SICSPAのようなジクロロアセチル保護されたアミン誘導体を用いて、アミンはまず脱保護を必要とし、これは室温の濃縮アンモニア水溶液中で夜通し培養することにより達成された。アンモニアはSpeedVac濃縮装置を介して除去された(水吸引器、その後、油真空ポンプが続く)。リンカー(つまり、SS-ビオチンまたはSS-PEG4-ビオチン)を含むジスルフィドを切断するために、dsDNAを37°Cで1時間DTT(30mMの最終濃度)を用いて処理した。骨格標識化については、骨格ホスホロチオエートを含むdsDNAを50°Cのリン酸標識緩衝液中で25mMのEZ-Linkヨードアセチル-PEG2-ビオチン(Thermo Scientific)で夜通しインキュベートし、生成物をQiagen PCR精製キットで精製した。付着したビオチン部分を操作するすべての反応をストレプトアビジンゲルシフトアッセイによって定量化した。
Claims (11)
- 第1の鎖と第2の鎖を含む二本鎖オリゴヌクレオチドであって、ここで、
(a)前記第1の鎖は第1の核酸塩基および第1の2’-デオキシリボシルを含み、当該第1の核酸塩基は以下の式を有し、
ここで波線は第1の2’-デオキシリボシルへの結合を示し、および
(b)前記第2の鎖は、第2の核酸塩基および第2の2’-デオキシリボシルを含み、当該第2の核酸塩基は以下の式からなる群から選択され、
- 第1の核酸塩基と第2の核酸塩基は二本鎖オリゴヌクレオチド中で塩基対を形成する、請求項1に記載の二本鎖オリゴヌクレオチド。
- R2は水素またはハロゲンである、請求項1又は2に記載の二本鎖オリゴヌクレオチド。
- R2は水素である、請求項1又は2に記載の二本鎖オリゴヌクレオチド。
- R2はハロゲンである、請求項1又は2に記載の二本鎖オリゴヌクレオチド。
- ハロゲンはフルオロである、請求項5に記載の二本鎖オリゴヌクレオチド。
- 第2の核酸塩基は以下である、請求項1-6のいずれか1つに記載の二本鎖オリゴヌクレオチド。
- 第2の核酸塩基は以下である、請求項7に記載の二本鎖オリゴヌクレオチド。
- 第2の核酸塩基は以下である、請求項7に記載の二本鎖オリゴヌクレオチド。
- 第2の核酸塩基は以下である、請求項7に記載の二本鎖オリゴヌクレオチド。
- 第2の核酸塩基は以下である、請求項7に記載の二本鎖オリゴヌクレオチド。
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