JP5837526B2 - 反応性非天然アミノ酸遺伝コード付加 - Google Patents
反応性非天然アミノ酸遺伝コード付加 Download PDFInfo
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- JP5837526B2 JP5837526B2 JP2013044435A JP2013044435A JP5837526B2 JP 5837526 B2 JP5837526 B2 JP 5837526B2 JP 2013044435 A JP2013044435 A JP 2013044435A JP 2013044435 A JP2013044435 A JP 2013044435A JP 5837526 B2 JP5837526 B2 JP 5837526B2
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Description
本願はUSSN60/479,931、発明の名称「真核遺伝コードの拡張(Expanding the Eukaryotic Genetic Code)」、発明者Chinら、出願日2003年6月18日;USSN60/493,014、発明の名称「真核遺伝コードの拡張(Expanding the Eukaryotic Genetic Code)」、発明者Chinら、出願日2003年8月5日;及びUSSN60/496,548、発明の名称「真核遺伝コードの拡張(Expanding the Eukaryotic Genetic Code)」、発明者Chinら、出願日2003年8月19日の各出願に基づく通常特許出願である。本願はこれらの各原出願の優先権と特典を主張する。
本発明は米国国立衛生研究所により交付された助成番号GM62159と、エネルギー省により交付された助成番号DE−FG0300ER45812として政府助成下に創出された。米国政府は本発明に所定の権利を有する。
本発明は真核細胞における翻訳生化学の分野に関する。本発明は真核細胞で直交tRNA、直交シンテターゼ及びその対を作製するための方法と組成物に関する。本発明は非天然アミノ酸の組成物、蛋白質、及び非天然アミノ酸を組込んだ蛋白質を真核細胞で生産する方法にも関する。
本発明を詳細に記載する前に、本発明は特定装置又は生物系に限定されず、当然のことながら種々のものに適用できると理解すべきである。同様に、本明細書で使用する用語は特定態様のみの説明を目的とし、限定的でないことも理解すべきである。本明細書と特許請求の範囲で使用する単数形はそうでないことが内容から明白である場合を除き、複数形も含む。従って、例えば「細胞」と言う場合には2個以上の細胞の組合せを含み、「細菌」と言う場合には細菌混合物を含み、他の用語についても同様である。
真核細胞で非天然アミノ酸を該当蛋白質又はポリペプチドに特異的に組込むためには、所望非天然アミノ酸のみをtRNAに負荷し、20種の標準アミノ酸は負荷しないようにシンテターゼの基質特異性を改変する。直交シンテターゼが無差別な場合には、ターゲット位置に天然アミノ酸と非天然アミノ酸の混合物を含む突然変異体蛋白質となる。本発明は特定非天然アミノ酸に対する基質特異性を改変した直交アミノアシルtRNAシンテターゼを作製する組成物と方法を提供する。
本発明は直交tRNA(O−tRNA)を含む真核細胞を提供する。直交tRNAはO−tRNAによりインビボ(in vivo)認識されるセレクターコドンを含むポリヌクレオチドによりコードされる蛋白質への非天然アミノ酸の組込みを媒介する。所定態様では、本発明のO−tRNAは配列番号65に記載のポリヌクレオチド配列を含むか又は前記配列から細胞でプロセシングされるtRNAの例えば少なくとも40%、少なくとも45%、少なくとも50%、少なくとも60%、少なくとも75%、少なくとも80%、又は90%以上の効率で非天然アミノ酸の蛋白質組込みを媒介する。本明細書の表5参照。
直交対はO−tRNA(例えばサプレッサーtRNA、フレームシフトtRNA等)とO−RSから構成される。O−tRNAは内在シンテターゼによりアシル化されず、O−tRNAによりインビボ(in vivo)認識されるセレクターコドンを含むポリヌクレオチドによりコードされる蛋白質への非天然アミノ酸の組込みを媒介することができる。O−RSはO−tRNAを認識し、真核細胞においてO−tRNAを非天然アミノ酸で優先的にアミノアシル化する。直交対の作製方法と前記方法により作製された直交対及び真核細胞で使用するための直交対の組成物も本発明に含まれる。多重直交tRNA/シンテターゼ対の開発により、真核細胞で各種コドンを使用して多重非天然アミノ酸の同時に組込みが可能になる。
忠実度とは所望分子(例えば非天然アミノ酸又はアミノ酸)が成長中のポリペプチドの所望位置に組込まれる確度を意味する。本発明の翻訳成分はセレクターコドンに応答して非天然アミノ酸を高い忠実度で蛋白質に組込む。例えば、本発明の成分を使用すると、(例えばセレクターコドンに応答して)成長中のポリペプチド鎖の所望位置に所望非天然アミノ酸が組込まれる効率は成長中のポリペプチド鎖の所望位置への特定天然アミノ酸の望ましくない組込みに比較して例えば>75%、>85%、>95%、又は>99%又はそれ以上である。
本発明の直交翻訳成分は一般に真核細胞又は翻訳系で使用するために非真核生物に由来する。例えば、直交O−tRNAは例えば真正細菌(例えば大腸菌(Escherichia coli)、サーマス・サーモフィルス(Thermus thermophilus)、バシラス・ステアロサーモフィラス(Bacillus stearothermophilus)等)や始原菌(例えばメタノコッカス・ヤナシイ(Methanococcus jannaschii)、メタノバクテリウム・テルモオートロフィカム(Methanobacterium thermoautotrophicum)、ハロバクテリウム(Halobacterium)(例えばハロフェラックス・ボルカニ(Haloferax volcanii)及びハロバクテリウム(Halobacterium)種NRC−1)、アルカエオグロブス・フルギドゥス(Archaeoglobus fulgidus)、ピュロコッカス・フリオスス(Pyrococcus furiosus)、ピュロコッカス・ホリコシ(Pyrococcus horikoshii)、アエロピュルム・ペルニクス(Aeuropyrum pernix)等)等の非真核生物に由来することができ、直交O−RSは例えば真正細菌(例えば大腸菌(Escherichia coli)、サーマス・サーモフィルス(Thermus thermophilus)、バシラス・ステアロサーモフィラス(Bacillus stearothermophilus)等)や始原菌(例えばメタノコッカス・ヤナシイ(Methanococcus jannaschii)、メタノバクテリウム・テルモオートロフィカム(Methanobacterium thermoautotrophicum)、ハロバクテリウム(Halobacterium)(例えばハロフェラックス・ボルカニ(Haloferax volcanii)及びハロバクテリウム(Halobacterium)種NRC−1)、アルカエオグロブス・フルギドゥス(Archaeoglobus fulgidus)、ピュロコッカス・フリオスス(Pyrococcus furiosus)、ピュロコッカス・ホリコシ(Pyrococcus horikoshii)、アエロピュルム・ペルニクス(Aeuropyrum pernix)等)等の非真核生物に由来することができる。あるいは、例えば植物、藻類、原生動物、真菌、酵母、動物(例えば哺乳動物、昆虫、節足動物等)等の真核資源も使用することができ、例えば成分は該当細胞もしくは翻訳系に直交であるか又は該当細胞もしくは翻訳系に直交となるように改変(例えば突然変異)されている。
本発明のセレクターコドンは蛋白質生合成機構の遺伝コドン枠を拡張する。例えば、セレクターコドンとしては例えばユニーク3塩基コドン、ナンセンスコドン(例えばアンバーコドン(UAG)又はオパールコドン(UGA)等の終止コドン)、非天然コドン、少なくとも4塩基のコドン、レアコドン等が挙げられる。例えば1個以上、2個以上、3個以上等の多数のセレクターコドンを所望遺伝子に導入することができる。1個の遺伝子が所与セレクターコドンの複数のコピーを含むこともできるし、複数の異なるセレクターコドン又はその任意組み合わせを含むこともできる。
本明細書で使用する非天然アミノ酸とはセレノシステイン及び/又はピロリジンと20種の遺伝的にコードされる以下のαアミノ酸、即ちアラニン、アルギニン、アスパラギン、アスパラギン酸、システイン、グルタミン、グルタミン酸、グリシン、ヒスチジン、イソロイシン、ロイシン、リジン、メチオニン、フェニルアラニン、プロリン、セリン、スレオニン、トリプトフアン、チロシン、バリン以外の任意アミノ酸、修飾アミノ酸又はアミノ酸類似体を意味する。αアミノ酸の一般構造は式I:
上記非天然アミノ酸の多くは例えばSigma(米国)やAldrich(Milwaukee,WI,米国)から市販されている。市販されていないものは場合により本明細書に記載する方法や各種刊行物に記載されている方法や当業者に公知の標準方法を使用して合成される。有機合成技術については例えばFessendonとFessendon著Organic Chemistry(1982, 第2版, Willard Grant Press, Boston Mass.);March著Advanced Organic Chemistry(第3版, 1985, Wiley and Sons, New York);及びCareyとSundberg著Advanced Organic Chemistry(第3版, Parts A and B, 1990, Plenum Press, New York)を参照されたい。非天然アミノ酸の合成について記載しているその他の刊行物としては例えばWO2002/085923,発明の名称「非天然アミノ酸のインビボ組込み(in vivo incorporation of unnatural amino acids)」;Matsoukasら, (1995) J. Med. Chem., 38, 4660-4669;King, F. E. & Kidd, D. A. A. (1949) A New Synthesis of Glutamine and of γ-Dipeptides of Glutamic Acid from Phthylated Intermediates. J. Chem. Soc., 3315-3319;Friedman, O. M. & Chatterrji, R. (1959) Synthesis of Derivatives of Glutamine as Model Substrates for Anti-Tumor Agents. J. Am. Chem. Soc. 81, 3750-3752;Craig, J. C. ら(1988) Absolute Configuration of the Enantiomers of 7-Chloro-4[[4-(diethylamino)-1-methylbutyl]amino]quinoline(Chloroquine). J. Org. Chem. 53, 1167-1170;Azoulay, M., Vilmont, M. & Frappier, F. (1991) Glutamine analogues as Potential Antimalarials., Eur. J. Med. Chem. 26, 201-5;Koskinen, A. M. P. & Rapoport, H. (1989) Synthesis of 4-Substituted Prolines as Conformationally Constrained Amino Acid Analogues. J. Org. Chem. 54, 1859-1866;Christie, B. D. & Rapoport, H. (1985) Synthesis of Optically Pure Pipecolates from L-Asparagine. Application to the Total Synthesis of(+)-Apovincamine through Amino Acid Decarbonylation and Iminium Ion Cyclization. J. Org. Chem. 1989:1859-1866;Bartonら, (1987) Synthesis of Novel α-Amino-Acids and Derivatives Using Radical Chemistry:Synthesis of L-and D-α-Amino-Adipic Acids, L-α-aminopimelic Acid and Appropriate Unsaturated Derivatives. Tetrahedron Lett. 43:4297-4308;及びSubasingheら, (1992) Quisqualic acid analogues:synthesis of beta-heterocyclic 2-aminopropanoic acid derivatives and their activity at a novel quisqualate-sensitized site. J. Med. Chem. 35:4602-7が挙げられる。2002年12月22日付け特許出願,発明の名称「蛋白質アレー(Protein Arrays)」(代理人整理番号P1001US00)も参照されたい。
真核細胞による非天然アミノ酸取り込みは例えば蛋白質に組込むように非天然アミノ酸を設計及び選択する場合に一般に考慮される問題の1つである。例えば、α−アミノ酸の電荷密度が高いと、これらの化合物は細胞に浸透しにくいと思われる。天然アミノ酸は一連の蛋白質輸送システムにより真核細胞に取り込まれる。非天然アミノ酸が細胞に取り込まれる場合にはどの非天然アミノ酸が取り込まれるかを判断する迅速なスクリーニングを実施することができる。例えば2002年12月22日付け特許出願,発明の名称「蛋白質アレー(Protein Arrays)」(代理人整理番号P1001US00);及びLiu, D. R. & Schultz, P. G. (1999) Progress toward the evolution of an organism with an expanded genetic code. PNAS United States 96-4780-4785における毒性アッセイ参照。取込みは種々の方法で容易に分析されるが、細胞取込み経路に利用可能な非天然アミノ酸を設計する代替方法は、アミノ酸をインビボ(in vivo)生産する生合成経路を提供する方法である。
細胞にはアミノ酸と他の化合物を生産するために多数の生合成経路が元々存在している。特定非天然アミノ酸の生合成法は自然界(例えば真核細胞中)には存在しないと思われるが、本発明はこのような方法を提供する。例えば、非天然アミノ酸の生合成経路は場合により新規酵素を付加するか又は既存宿主細胞経路を改変することにより宿主細胞で作製される。付加新規酵素は場合により天然酵素又は人工的に進化させた酵素である。例えば、(WO2002/085923、発明の名称「非天然アミノ酸のインビボ組込み(in vivo incorporation of unnatural amino acids)」の実施例に記載されているような)p−アミノフェニルアラニンの生合成は他の生物に由来する公知酵素の組合せの付加に依存している。これらの酵素の遺伝子はこの遺伝子を含むプラスミドで細胞を形質転換することにより真核細胞に導入することができる。遺伝子は細胞で発現されると、所望化合物を合成するための酵素経路を提供する。場合により付加される酵素種の例は下記実施例に記載する。その他の酵素配列は例えばGenbankから入手できる。人工的に進化させた酵素も場合により同様に細胞に付加する。このように、非天然アミノ酸を生産するように細胞機構と細胞資源を操作する。
少なくとも1種の非天然アミノ酸を組込んだ該当蛋白質又はポリペプチドが本発明の特徴である。本発明は本発明の組成物と方法を使用して生産された少なくとも1種の非天然アミノ酸を組込んだポリペプチド又は蛋白質も含む。賦形剤(例えば医薬的に許容可能な賦形剤)も蛋白質に加えることができる。
本発明の蛋白質(例えば非天然アミノ酸を組込んだ蛋白質、非天然アミノ酸を組込んだ蛋白質に対する抗体等)は当業者に使用されている公知標準手順に従って部分的又は実質的に均質まで精製することができる。従って、本発明のポリペプチドは当分野で周知の多数の方法の任意のものにより回収及び精製することができ、このような方法としては例えば硫安又はエタノール沈殿、酸又は塩基抽出、カラムクラマトグラフィー、アフィニティーカラムクラマトグラフィー、アニオン又はカチオン交換クロマトグラフィー、ホスホセルロースクロマトグラフィー、疎水性相互作用クロマトグラフィー、ヒドロキシアパタイトクロマトグラフィー、レクチンクロマトグラフィー、ゲル電気泳動等が挙げられる。所望により蛋白質リフォールディング段階を使用して正しく折畳まれた成熟蛋白質を作製することができる。高純度が所望される最終精製段階では、高性能液体クロマトグラフィー(HPLC)、アフィニティークロマトグラフィー又は他の適切な方法を使用することができる。1態様では、例えば1種以上の非天然アミノ酸を組込んだ蛋白質をアフィニティー精製するために、非天然アミノ酸(又は非天然アミノ酸を組込んだ蛋白質)に対して作製した抗体を精製試薬として使用する。所望に応じて部分的又は均質まで精製した後、ポリペプチドを場合により例えばアッセイ成分、治療試薬又は抗体生産用免疫原として使用する。
1側面では、本発明は本発明の分子(例えばシンテターゼ、tRNA、及び非天然アミノ酸を組込んだ蛋白質)に対する抗体を提供する。本発明の分子に対する抗体は例えば本発明の分子を精製するための精製試薬として有用である。更に、抗体は例えば前記分子の存在又は位置を(例えばインビボ(in vivo)又はインサイツ(in situ)で)追跡するために、シンテターゼ、tRNA、及び非天然アミノ酸を組込んだ蛋白質の存在を指示するための指示試薬として使用することができる。
本発明のポリペプチドは(例えば本発明の翻訳系で合成される蛋白質の場合には非天然アミノ酸を含み、例えば本発明の新規シンテターゼの場合には標準アミノ酸の新規配列を含む)種々の新規ポリペプチド配列を提供するので、ポリペプチドは例えばイムノアッセイで認識することができる新規構造特徴も提供する。本発明のポリペプチドに特異的に結合する抗体の作製又は抗体と前記抗体又は抗血清と結合したポリペプチドも本発明の特徴の1つである。
本発明のポリペプチド又は蛋白質(例えばシンテターゼ、1種以上の非天然アミノ酸を組込んだ蛋白質等)は場合により例えば適切な医薬キャリヤーと共に治療用に使用される。このような組成物は例えば治療有効量の化合物と医薬的に許容可能なキャリヤー又は賦形剤を含有する。このようなキャリヤー又は賦形剤としては限定されないが、食塩水、緩衝食塩水、デキストロース、水、グリセロール、エタノール及び/又はその組合せが挙げられる。製剤は投与方法に合わせて製造される。一般に、蛋白質の投与方法は当分野で周知であり、本発明のポリペプチドの投与に適用することができる。
上記及び下記に記載するように、本発明は核酸ポリヌクレオチド配列及びポリペプチドアミノ酸配列(例えばO−tRNA及びO−RS)と、例えば前記配列を含む組成物及び方法を提供する。前記配列(例えばO−tRNA及びO−RS)の例を本明細書に開示する(表5,例えば配列番号3−65,86,並びに配列番号1及び2以外の配列参照)。しかし、当業者に自明の通り、本発明は本明細書(例えば実施例と表5)に開示する配列に限定されない。当業者に自明の通り、本発明は本明細書に記載する機能をもつ(例えばO−tRNA又はO−RSをコードする)多数の関連及び非関連配列も提供する。
遺伝コードの縮重により、「サイレント置換」(即ちコードされるポリペプチドに変化を生じない核酸配列の置換)はアミノ酸をコードする全核酸配列の暗黙の特徴である。同様に、「保存アミノ酸置換」はアミノ酸配列中の1又は数個のアミノ酸を高度に類似する特性をもつ別のアミノ酸で置換するものであり、このような置換も開示構築物と高度に類似することが容易に認められる。各開示配列のこのような保存変異は本発明の特徴である。
比較ハイブリダイゼーションを使用して本発明の核酸の保存変異体を含む本発明の核酸を同定することができ、この比較ハイブリダイゼーション法は本発明の核酸を識別する好適な方法である。更に、高、超高及び超々高ストリンジェンシー条件下で配列番号3−35(例えば3−19、20−35、又は配列3−35の他の任意サブセット)、64−85により示す核酸とハイブリダイズするターゲット核酸も本発明の特徴である。このような核酸の例としては所与核酸配列と比較して1又は数個のサイレント又は保存核酸置換をもつものが挙げられる。
1側面では、本発明は本明細書に開示するO−tRNA及びO−RSの配列から選択される核酸中にユニークサブ配列を含む核酸を提供する。ユニークサブ配列は任意公知O−tRNA及びO−RS核酸配列に対応する核酸に比較してユニークである。例えばデフォルトパラメーターに設定したBLASTを使用してアラインメントを実施することができる。任意ユニークサブ配列は例えば本発明の核酸を同定するためのプローブとして有用である。
2種以上の核酸又はポリペプチド配列に関して「一致」又は「一致度」百分率なる用語は2種以上の配列又はサブ配列を最大限に対応するように対比及び整列させ、以下に記載する配列比較アルゴリズム(又は当業者に入手可能な他のアルゴリズム)の1種を使用するか又は目視により測定した場合に相互に同一であるか又は同一のアミノ酸残基もしくはヌクレオチドの百分率が特定値であることを意味する。
突然変異誘発及び他の分子生物学技術
キットも本発明の特徴である。例えば、少なくとも1種の非天然アミノ酸を組込んだ蛋白質を細胞で生産するためのキットが提供され、前記キットはO−tRNAをコードするポリヌクレオチド配列、及び/又はO−tRNA、及び/又はO−RSをコードするポリヌクレオチド配列、及び/又はO−RSを収容する容器を含む。1態様では、キットは更に少なくとも1種の非天然アミノ酸を含む。別の態様では、キットは更に蛋白質を生産するための説明書を含む。
新規な物理的、化学的又は生物学的性質をもつ非天然アミノ酸を付加するような真核遺伝コードの拡張は、これらの細胞における蛋白質機能を分析及び制御するための強力なツールとなろう。この目的のために、サッカロマイセス・セレビシエ(Saccharomyces cerevisiae)でアンバーコドンに応答して高い忠実度で非天然アミノ酸を蛋白質に組込むアミノアシルtRNAシンテターゼを単離するための一般アプローチについて記載する。この方法はGAL4のDNA結合ドメインと転写活性化ドメインの間のアンバーコドンの抑圧によるGAL4応答性レポーター遺伝子HIS3、URA3又はLacZの活性化に基づく。活性大腸菌チロシル−tRNAシンテターゼ(EcTyrRS)変異体のポジティブ選択のためのGAL4レポーターの最適化について記載する。「毒性対立遺伝子」として増殖培地に添加した小分子(5−フルオロオロト酸(5−FOA))の使用によりURA3レポーターを用いて不活性EcTyrRS変異体のネガティブ選択も行った。重要な点として、ポジティブ選択とネガティブ選択の両者を単一細胞で一連のストリンジェンシー下に実施することができる。このため、突然変異体シンテターゼの大きなライブラリーから一連のアミノアシルtRNAシンテターゼ(aaRS)活性を容易に単離できる。所望aaRS表現型を単離するこの方法の能力をモデル選択により立証する。
構成的ADH1プロモーターの制御下にEcTyrRS遺伝子を発現させ、同一の高コピー酵母プラスミド(pEcTyrRStRNACUA,図1C)からtRNACUA遺伝子を発現させた。キメラGAL構築物のDNA結合ドメインと活性化ドメインの間に単一アンバー突然変異を含む低コピーレポーターとpEcTyrRStRNACUAをMaV203に同時形質転換すると、細胞はヒスチジンを加えず、10−20mM 3−ATを添加した培地で増殖した(図2)。MaV203細胞を同一GAL4構築物と不活性シンテターゼ突然変異体(A5)又はEctRNA遺伝子を欠失する構築物のいずれかで形質転換すると、10mM 3−ATで増殖は観察されなかった(図2)。これらの実験から明らかなように、ADH1プロモーターからEcTyrRSを機能的形態で構成的に発現させることができ、MaV203における内在アンバー抑圧は最小であり、このシステムではEctRNACUAは酵母シンテターゼにより殆ど負荷されない。例えば、H. Edwardsら, (1991), An Escherichia coli tyrosine transfer RNA is a leucine-specific transfer RNA in the yeast Saccharomyces cerevisiae, Proc. Natl. Acad. Sci. U. S. A. 88:1153-1156;及びH. Edwards, & P. Schimmel, (1990), A bacterial amber suppressor in Saccharomyces cerevisiae is selectively recognized by a bacterial aminoacyl-tRNA synthetase, Molecular & Cellular Biology 10:1633-1641参照。EcTyrRSはS.cerevisiae tRNAに負荷しない(例えば、Y. Kwok, & J. T. Wong, (1980), Evolutionary relationship between Halobacterium cutirubrum and eukaryotes determined by the use of aminoacyl-tRNA synthetases as phylogenetic probes, Canadian Journal of Biochemistry 58:213-218;B. P. Doctorら, (1966), Studies on the species specificity of yeast and E. coli tyrosine tRNAs, Cold Spring Harbor Symp. Quant. Biol. 31:543-548;及びK. Wakasugiら, (1998), Genetic code in evolution:switching species-specific aminoacylation with a peptide transplant, EMBO Journal 17:297-305)ので、これらの実験はEcTyrRS/EctRNACUAがS.cerevisiaeにおいて直交対であることを裏付けるものである。
ベクター構築
pESCSU3URAに由来するプライマーtRNA5’:GGGGGGACCGGTGGGGGGACCGGTAAGCTTCCCGATAAGGGAGCAGGCCAGTAAAAAGCATTACCCCGTGGTGGGTTCCCGA(配列番号89)、及びtRNA3’:GGCGGCGCTAGCAAGCTTCCCGATAAGGGAGCAGGCCAGTAAAAAGGGAAGTTCAGGGACTTTTGAAAAAAATGGTGGTGGGGGAAGGAT(配列番号90)を使用してtRNACUA遺伝子をPCRにより増幅した。この反応及び他の全PCR反応はRoche製品Expand PCRキットを製造業者の指示に従って使用して実施した。NheIとAgeIで制限エンドヌクレアーゼ消化後に、このtRNA遺伝子を2μmベクターpESCTrp(Stratagene)の同一部位間に挿入し、ptRNACUAを得た。プライマーADHf:IGGGGGGACCGGTIGGGGGGACCGGTCGGGATCGAAGAAATGATGGTAAATGAAATAGGAAATCAAGG(配列番号91)及びpADHR:GGGGGGGAATTCAGTTGATTGTATGCTTGGTATAGCTTGAAATATTGTGCAGAA AAAGAAAC(配列番号92)を使用してpDBLeu(Invitrogen)から全長ADH1プロモーターをPCRにより増幅し、AgeIとEcoRIで消化した。プライマーpESCTrp1:TCATAACGAGAATTCCGGGATCGAAGAAATGATGGTAAATGAAATAGGAAATCTCATAACGAGAATTCATGGCAAGCAGTAACTTG(配列番号93)及びpESCTrp2:TTACTACGTGCGGCCGCATGGCAAGCAGTAACTTGTTACTACGTGCG GCCGCTTATTTCCAGCAAATCAGAC(配列番号94)を使用してEcTyrRSを増幅した。EcTyrRS PCR産物をEcoRIとNotIで消化した。ptRNACUAを次にAgeIとNotIで消化した。これらの3種のDNAの三重ライゲーションにより、pEcTyrRS−tRNACUAを得た。オリゴヌクレオチドF37Afwd:CCGATCGCGCTCGCTTGCGGCTTCGATC(配列番号95)、N126Afwd:ATCGCGGCGAACGCCTATGACTGGTTC(配列番号96)、182,183,186A,GTTGCAGGGTTATGCCGCCGCCTGTGCGAACAAACAGTAC(配列番号97)及びその逆相補配列と、フランキングオリゴヌクレオチド4783:GCCGCTTTGCTATCAAGTATAAATAG(配列番号98)、3256:CAAGCCGACAACCTTGATTGG(配列番号99)と鋳型としてpEcTyrRS−tRNACUAを使用して活性部位のアミノ酸残基37,126,182,183及び186をアラニンに突然変異させたプラスミドpA5−tRNACUAをオーバーラップPCRにより作製した。PCR産物をEcoRIとNotIで消化し、同一酵素で消化して単離したpEcTyrRS−tRNACUAの大きいフラグメントにライゲートした。第1世代DB−ADレポーターを構築するために、フォワードプライマーpADfwd:GGGGACAAGTTTGTACAAAAAAGCAGGCTACGCCAATTTTAATCAAAGTGGGAATATTGC(配列番号100)又はpADfwd(TAG)GGGGACAAGTTTGTACAAAAAAGCAGGCTAGGCCAATTTTAATCAAAGTGG GAATATTGC(配列番号101)とADrev:GGGGACCACTTTGTACAAGAAAGCTGGGTTACTCTTTTTTTGGGTTTGGTGG GGTATC(配列番号102)を使用してpGADT7(Clontech)からGAL4 DNA結合ドメインをPCR増幅した。Clonase法を製造業者の指示に従って使用してこれらのPCR産物をベクターpDEST3−2(invitrogen)にクローニングし、pDB−ADとpDB−(TAG)−ADを得た。PGADGAL4と変異体を構築するために、プライマーADH1428−1429 AAGCTATACCAAGCATACAATC(配列番号103)、及びGAL4C:ACAAGGCCTTGCTAGCTTACTCTTTTTTTGGGTTTGGTGGGGTATCTTC(配列番号104)を使用してGAL4遺伝子をpCL1(Clontech)からPCRにより増幅した。このフラグメントをベクターpCR2.1 TOPO(Invitrogen)に製造業者の指示に従ってクローニングした。GAL4遺伝子を含むクローン(pCR2.1TOPOGAL4)をHindIIIで消化し、2.7kb GAL4フラグメントをゲル精製し、予めHindIIIで消化して仔ウシ腸ホスファターゼで処理してゲル精製しておいたpGADT7の大きいフラグメントにライゲートした。添付情報に記載されているプライマーを使用してQuikchange反応(Stratagene)を製造業者の指示に従ってpCR2.1で実施することによりGAL4遺伝子の変異体を作製した。GAL4突然変異体を野生型GAL4遺伝子と同様にpGADT7にクローニングした。全最終構築物をDNAシーケンシングにより確認した。
S.cerevisiae株MaV203,(Invitrogen)はMATα;leu2−3,112;trp1109;his3 Δ200;ade2−101;cyh2R;cyh1R;GAL4Δ;gal80Δ;GAL1::lacZ;HIS3UASGAL1::HIS3@LYS2;SPAL10UASGAL1::URA3である。酵母培地はClontechから購入し、5−FOAとX−GALはInvitrogenから購入し、3−ATはBIO 101から購入した。YPER(Yeast Protein Extraction Reagent)とONPGはPierce Chemicalsから購入した。プラスミド形質転換はPEG/リチウム酢酸法(例えばD. Burkeら, (2000)Methods in Yeast Genetics. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY参照)により実施し、形質転換細胞は適当な合成完全ドロップアウト培地で選択した。MaV203で各種プラスミド組み合わせにより付与される表現型を試験するために、各形質転換の合成完全ドロップアウトプレートからの酵母コロニーを滅菌水15μLに再懸濁し、該当選択培地でストリークした。各表現型を少なくとも5個の独立コロニーで確認した。X−GALアッセイはアガロース重層法により実施した。I. G. Serebriiskii, & E. A. Golemis, (2000), Uses of lacZ to study gene function:evaluation of beta-galactosidase assays employed in the yeast two-hybrid system, Analytical Biochemistry 285:1-15参照。要約すると、ニートクロロホルムを数回加えることによりコロニー又は細胞パッチを寒天プレート上で溶解させた。クロロホルムの蒸発後、0.1M Na2PO4で緩衝した0.25g/L XGAL含有1%アガロースをプレート表面に添加した。アガロースが固まったら、プレートを37℃で12時間インキュベートした。96ウェルブロックのSD−leu,−trp1mLにコロニー1個を接種することによりONPGアッセイを実施し、30℃で振盪下にインキュベートした。細胞100μLのOD660と数回の細胞希釈倍率を96ウェルマイクロタイタープレートで平行して記録した。細胞(100μL)をYPER:ONPG(1X PBS,50% v/v YPER,20mM MgCl2,0.25% v/v β−メルカプトエタノール,及び3mM ONPG)100μLと混合し、37℃で振盪下にインキュベートした。発色後、細胞を遠心によりペレット化し、上清を清浄な96ウェルマイクロタイタープレート(Nunclon,cat.#167008)に移し、A420を記録した。記載する全データは少なくとも4個の独立クローンからの試験の平均であり、記載する誤差線は標準偏差を表す。ONPG加水分解は式:β−ガラクトシダーゼ単位=1000.A420/(V.t.OD660)(式中、Vはmlで表した細胞容量であり、tは分で表したインキュベーション時間である)を使用して計算した。例えば、I. G. Serebriiskii, & E. A. Golemis, (2000), Uses of lacZ to study gene function:evaluation of beta-galactosidase assays employed in the yeast two-hybrid system, Analytical Biochemistry 285:1-15参照。β−ガラクトシダーゼ1単位は1μmol ONPG/分/細胞の加水分解に対応する。Serebriiskii and Golemis,前出参照。分光光度読み取りはSPECTRAmax190プレートリーダーを使用して実施した。
ポジティブ選択:2種の一晩培養液をSD−Leu,−Trpで増殖させた。一方はpEcTyrRS−tRNACUA/pGADGAL4(T44,R110TAG)を接種したMaV203を含み、他方はpA5−tRNASU3/pGADGAL4(T44,R110TAG)を接種した。これらの細胞を遠心により回収し、ボルテックスにより0.9% NaClに再懸濁した。次に2種の細胞溶液を等しくOD660まで希釈した。pEcTyrRS−tRNACUA/pGADGAL4(T44,R110TAG)を含むMaV203を107倍以上に連続希釈した後、pA5−tRNACUA/pGADGAL4(T44,R110TAG)を含む未希釈MaV203と各希釈液を1:1 vol:volで混合し、活性チロシル−tRNAシンテターゼと不活性チロシル−tRNAシンテターゼを含む規定比の細胞を得た。各比について2回目の連続希釈を実施し、pEcTyrRS−tRNACUA/pGADGAL4(T44,R110TAG)を含む細胞とpA5−tRNACUA/pGADGAL4(T44,R110TAG)を含む細胞の比を維持しながら細胞数を減らした。これらの希釈液をSD−Leu,−trp,SD−Leu,−Trp,−URAとSD−Leu,−Trp,−His+50mM 3−ATにプレーティングした。60時間後にEagle Eye CCDカメラ(Stratagene)を使用して各プレートのコロニー数をカウントし、生存細胞の表現型をX−GAL β−ガラクトシダーゼアッセイで確認した。数個の独立した青色又は白色コロニーからの細胞を単離し、SD−leu,−trpで飽和まで増殖させ、プラスミドDNAを標準法により単離した。EcTyrRS変異体をDNAシーケンシングにより確認した。
非天然アミノ酸をサッカロマイセス・セレビシエ(Saccharomyces cerevisiae)の遺伝コードに付加するための一般的で迅速な方法について記載する。5種のアミノ酸がナンセンスコドンTAGに応答して高い忠実度で効率的に蛋白質に組込まれている。これらのアミノ酸の側鎖は広範な化学的プローブ及び試薬でユニークにインビトロ(in vitro)及びインビボ(in vivo)修飾することができるケト基と;構造試験用重原子含有アミノ酸と;蛋白質相互作用の細胞内試験用光架橋剤を含む。この方法は酵母で蛋白質構造及び機能を操作する能力に及ぼす遺伝コードの制約を取り除くだけでなく、多細胞真核生物の遺伝コードの体系的拡張の糸口となる。
[3+2]シクロ付加に基づく蛋白質への部位特異的で迅速で確実で不可逆的なバイオコンジュゲーション法を立証する。生理的条件下で高度に選択的に蛋白質を修飾する化学反応が大いに必要とされている。例えばLemineux,& Bertozzi,(1996)TIBTECH,16:506−513参照。蛋白質の選択的修飾に現在使用されている大半の反応は求核反応パートナーと求電子反応パートナーの間の共有結合形成、例えばα−ハロケトンとヒスチジン又はシステイン側鎖の反応を利用している。これらの場合の選択性は蛋白質中の求核残基の数とアクセシビリティにより決定される。合成又は半合成蛋白質の場合には、非天然ケトアミノ酸とヒドラジド又はアミノオキシ化合物の反応等の他のより選択的な反応を使用することができる。例えばCornishら,(1996)Am.Chem.Soc.,118:8150−8151;及びMahalら,(1997)Science,276:1125−1128参照。最近、アミノ酸特異性を改変した直交tRNA−シンテターゼ対を使用して細菌と酵母でケトン含有アミノ酸(例えばWangら,(2003)Proc.Natl.Acad.Sci.,100:56−61;Zhangら,(2003)Biochemistry,42:6735−6746;及びChinら,(2003)Science,印刷中参照)を含む非天然アミノ酸を遺伝的にコードすることが可能になった(例えばWangら,(2001)Science 292:498−500;Chinら,(2002)Am.Chem.Soc.124:9026−9027;及びChinら,(2002)Proc.Natl.Acad.Sci.,99:11020−11024参照)。この方法により、フルオロフォア、架橋剤及び細胞傷害性分子等の多数の試薬でほぼ任意の蛋白質を選択的に標識することが可能になった。
本発明の1側面では、本発明はアルキニルアミノ酸を提供する。アルキニルアミノ酸の構造の1例は式IV:
1側面では、本発明は付加置換基分子に結合した非天然アミノ酸を含む蛋白質の製造方法と関連組成物を提供する。例えば、[3+2]シクロ付加により付加置換基を非天然アミノ酸に付加することができる。例えば図16参照。例えば、(例えばアジド基又は三重結合等の第1の反応基をもつ)非天然アミノ酸を組込んだ蛋白質への(例えばアルキン三重結合又はアジド基等の第2の反応基をもつ)所望分子の[3+2]シクロ付加は[3+2]シクロ付加反応について公開されている条件に従って実施することができる。例えば、PB緩衝液(pH=8)中に非天然アミノ酸を含む蛋白質をCuSO4、所望分子、及びCu線に加える。混合物を(例えば室温もしくは37℃で4時間又は4℃で一晩)インキュベートした後に、H2Oを加え、混合物を透析膜で濾過する。サンプルの付加を例えばゲル分析により分析することができる。
代表的O−tRNAとしては配列番号65か挙げられる(表5参照)。代表的O−RSとしては配列番号36−63,86が挙げられる(表5参照)。O−RS又はその部分(例えば活性部位)をコードするポリヌクレオチドの例としては配列番号3−35が挙げられる。更に、O−RSの代表的アミノ酸置換を表6に示す。
Claims (6)
- 少なくとも1つの非天然アミノ酸を含む少なくとも1つのタンパク質、抗体又は抗体フラグメントを真核細胞内で作製する方法であって、
少なくとも1つのセレクターコドンを含み、前記タンパク質、抗体又は抗体フラグメントをコードする核酸を含む真核細胞を、適切な培地で培養することを含み、ここで前記培地は、前記非天然アミノ酸を含み、前記真核細胞は、前記真核細胞内で機能し、前記セレクターコドンを認識する直交tRNA(O−tRNA)と、前記O−tRNAを前記非天然アミノ酸で優先的にアミノアシル化する直交アミノアシルtRNAシンテターゼ(O−RS)とを含み、前記O−RSは、配列番号48〜63の何れか一つに記載のアミノ酸配列を含む、方法。 - 少なくとも1つの非天然アミノ酸を含む少なくとも1つのタンパク質、抗体又は抗体フラグメントを作製する方法であって、
少なくとも1つのセレクターコドンを含み、前記タンパク質、抗体又は抗体フラグメントをコードする核酸を含む真核細胞を、適切な培地で培養し、ここで前記培地は、前記非天然アミノ酸を含み、前記真核細胞は、前記真核細胞内で機能し、前記セレクターコドンを認識する直交tRNA(O−tRNA)と、前記O−tRNAを前記非天然アミノ酸で優先的にアミノアシル化する直交アミノアシルtRNAシンテターゼ(O−RS)とを含み、
前記真核細胞内で、前記タンパク質、抗体又は抗体フラグメント内に、前記非天然アミノ酸を組み込み、ここで前記非天然アミノ酸は第一の反応基を含み、
前記タンパク質、抗体又は抗体フラグメントを、第二の反応基を含む分子と接触させ、ここで前記第一の反応基が、前記第二の反応基と反応することにより、前記分子が前記非天然アミノ酸に[3+2]シクロ付加反応を介して付着されることを含み、ここで
(a)前記O−RS又はその部分が、配列番号20〜35の何れか一つに記載のポリヌクレオチド配列によりコードされるか;
(b)前記O−RSが、配列番号48〜63の何れか一つに記載のアミノ酸配列を含むか;或いは
(c)前記O−RSが、配列番号2と少なくとも98%同一のアミノ酸配列を含むとともに、
大腸菌(E. coli)TyrRSのTyr37に対応する位置のグリシン、セリン、又はアラニン、
大腸菌(E. coli)TyrRSのAsn126に対応する位置のアスパラギン酸;
大腸菌(E. coli)TyrRSのAsp182に対応する位置のアスパラギン;
大腸菌(E. coli)TyrRSのPhe183に対応する位置のアラニン又はバリン;及び
大腸菌(E. coli)TyrRSのLeu186に対応する位置のメチオニン、バリン、システイン、又はスレオニン
から選択される2以上のアミノ酸を含む、方法。 - 前記分子が、有機小分子、細胞傷害性化合物、第二のタンパク質又はポリペプチド、及びプロドラッグからなる群より選択される、請求項2に記載の方法。
- 前記第一の反応基がアルキニル又はアジド部分であり、前記第二の反応基がアジド又はアルキニル部分である、請求項2に記載の方法。
- 前記非天然アミノ酸が、p−アジド−L−フェニルアラニン、p−ベンゾイル−フェニルアラニン又はp−プロパルギルオキシフェニルアラニンである、請求項2に記載の方法。
- 前記シクロ付加反応が、真核細胞内でインビボで行われる少なくとも1つの翻訳後修飾を含む、請求項2に記載の方法。
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