JP2015514706A - クリック核酸 - Google Patents
クリック核酸 Download PDFInfo
- Publication number
- JP2015514706A JP2015514706A JP2015503259A JP2015503259A JP2015514706A JP 2015514706 A JP2015514706 A JP 2015514706A JP 2015503259 A JP2015503259 A JP 2015503259A JP 2015503259 A JP2015503259 A JP 2015503259A JP 2015514706 A JP2015514706 A JP 2015514706A
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- Prior art keywords
- nucleic acid
- click
- thiol
- acid monomer
- cna
- Prior art date
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Abstract
Description
関連出願の相互参照
本明細書で示される核酸配列およびアミノ酸配列は、米国特許法施行規則1.822条に定義されたヌクレオチド塩基およびアミノ酸の標準的な文字略号を用いて示される。各核酸配列の一方の鎖のみが示されるが、表示の鎖へのいかなる参照によってもその相補鎖が含まれることは理解される。配列表は、2013年3月11日に作成された、1キロバイトの、参照により本明細書に組み入れられている、COL_0110WP_ST25.txtという名称のファイルの形式でASCIIテキストファイルとして提出される。
以下の用語および略語の説明は、本開示をより良く説明し、本開示の実施に際して当業者を手引きするために、提供される。本明細書で使用される場合、「含んで成る(comprising)」とは「含む(including)」を意味し、単数形「a」もしくは「an」または「the」は、文脈によって特に明示されない限り複数形の照応も含む。用語「or」は、別段の明確な指示が無い限り、表示された選択肢である要素のうちの単一の要素または2つ以上の要素の組合せを指す。
A. 序論
クリック核酸(CNA)分子、そのような分子を作製する方法およびその使用が開示される。本明細書に記載されるように、新規のCNA分子を作製するチオールクリックケミストリーとオリゴヌクレオチド合成との相乗的な組合せは、数え切れないほどの利点を有しており、重要な技術革新である。PNAは非生物学的なオリゴヌクレオチドが非常に有用であることを示したが、それらの合成法、利用できる骨格化学の制限、および固相反応の必要性は、それらの広範な実施を著しく制限している。対照的に、本明細書で開示されるクリックケミストリー法の使用は化学量論比の反応物の実現を可能にし、定量的変換の同時達成は多大なる新規性および価値の両方を有している。具体的には、チオール−クリックケミストリー反応の簡易さ、頑強さ、速さ、および化学量論的特徴は、チオール−クリックケミストリー反応を、新規のクラスの機能的オリゴヌクレオチド模倣剤の開発に最適なものにしている。実際に、これらの利点および化学的方法に基づいて、初期のポリCNA分子は$10〜100/グラムの推定現在価格で、10mg/バッチスケールで、容易に生産されたが、一方で、同一のDNA配列は$100,000/グラム近く費用がかかるであろう。この費用差は、その多大な費用のためにDNAを簡単には考慮することができない膨大な応用において、CNAを機能分子たらしめるものである。
所望の塩基配列を形成するためにチオール−エン「クリック」反応を利用している、新規クラスの生体機能的オリゴヌクレオチド、チオ−エーテル核酸あるいはCNAが本明細書で開示される。このアプローチ(その1例がDNAおよびPNA構造に並んで図示される)は図1に示されており、その重要性を強めるいくつかの明確な利点を有しており、具体的には、(i)クリックケミストリーの使用、(ii)反応を光開始する能力、および(iii)CNA分子の安定性を増強するチオ−エーテル骨格を有する重合体の形成である。
i. インビトロにおけるCNA応用の例
CNA応用には、生物学的検出、SELEX様プロセスの開発、および相補的なDNAまたはCNA配列の複製が含まれる。PCRと同様の増幅および結果を目標にして、オリゴマーCNAのインサイチュハイブリダイゼーションおよび選択的ライゲーションによって、相補的なDNAまたはCNA鎖からCNA鎖が複製される、指数関数的増幅プロセスが得られる。このプロセスは、大量の高分子量配列を生成する1つの手段として機能し、基質増幅が検出に重要となる生物学的検出における実行に適している。
開示のCNA分子は、標的核酸への結合およびその検出をすることが可能なプローブおよび/またはプライマーとして使用することができる。例えばサザンブロットおよび他の応用のためにはより長いおよび/またはより短い配列も考えられるが、典型的には、そのようなプローブおよびプライマーは、6〜40ヌクレオチド長、例えば、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28 29、30、31、32、32、34、35、36、37、38、39、または40ヌクレオチド長であり、標的核酸にハイブリダイズすることが可能である。従って、いくつかの例では、プローブまたはプライマーは40ヌクレオチド長よりも大きく、例えば、少なくとも50ヌクレオチド長、少なくとも60ヌクレオチド長、少なくとも70ヌクレオチド長、少なくとも80ヌクレオチド長、少なくとも90ヌクレオチド長、少なくとも100ヌクレオチド長、少なくとも150ヌクレオチド長、少なくとも200ヌクレオチド長、少なくとも250ヌクレオチド長、少なくとも500ヌクレオチド長、またはさらには少なくとも1000ヌクレオチド長である。
本明細書で開示されるCNA分子プライマーおよびプローブの主な応用は、試料(例えば、生物試料)中の標的核酸の検出である。本明細書に記載の方法は、検査室および臨床環境等における診断応用および予後診断応用を含む、標的核酸の検出が望まれるあらゆる目的に使用することができる。適切な試料には、あらゆる従来の環境試料または生物試料、例えば、ヒト対象または動物対象から得られる臨床試料、例えば、限定はされないが、細胞、組織(例えば、肺、肝臓および腎臓)、骨髄穿刺液、体液(例えば、血液、血清、尿、脳脊髄液、気管支肺胞洗浄液、気管吸引物、痰、鼻咽頭吸引物、中咽頭吸引物、唾液)、眼スワブ、頸部スワブ、膣スワブ、直腸スワブ、便、および便懸濁液が含まれる。
また、標的核酸を検出するための複数の同種または異種CNAプローブを含有するアレイが開示される。アレイは、基板上のアドレス可能な位置の並びであり、各アドレスはCNA(例えば、プローブ)を含有する。いくつかの実施形態において、特定のCNAが複数のアドレスで重複して含有される場合もあるが、各アドレスは単一のタイプまたはクラスのCNA(例えば、単一プローブ)に対応している。「マイクロアレイ」は、ハイブリダイゼーションの検出に顕微鏡検査を必要とする小型化されたアレイである。より大型の「マクロアレイ」は各アドレスがヒトの肉眼によって認識可能になることを可能にし、いくつかの実施形態において、ハイブリダイゼーションシグナルはさらなる拡大無しで検出可能である。アドレスは、標識されていてもよく、別個のガイドで識別できるようにされていてもよく、あるいはその他の方法で位置による特定がされてもよい。
開示のCNA分子は、核酸の折り紙および定方向構築応用において、例えば核酸ステープルとして使用することができる。核酸折り紙は、ナノスケールで任意の二次元および三次元の形状を作製するための、ナノスケールの核酸折り畳みである。相補的な塩基対間の相互作用の特異性により、その塩基配列の設計を通じて、DNAは有用な構築材料となる。核酸折り紙は、複数のより小さな「ステープル」鎖の助けによる、長い単鎖ウイルスDNAの折り畳みを含む。いくつかの例では、単一の長いDNA分子で満たされたラスターを用いて画像が描かれる。次にこのデザインは、個々のステープル鎖の配置を算出するコンピュータプログラムに送り込まれる。各ステープルは鋳型DNAの特異的な領域に結合し、そのため、ワトソンクリック塩基対合によって、全ステープル鎖の必要な配列が認識および表示される。DNAは混合された後、加熱および冷却される。DNAが冷却されるにつれて、種々のステープルが長鎖を所望の形状に引き込む。デザインは、原子間力顕微鏡法、またはDNAが蛍光物質に結合される蛍光顕微鏡法を含むいくつかの方法によって直接観察することができる。
CNAの独特な化学的性質および物理的性質を考慮すると、CNAは、インビボにおける応用にかなりの可能性を有している。CNAが外側の細胞膜を横断可能であるのは興味深いことである。CNAの疎水性および中性の骨格を考慮すると、CNAは細胞の脂質膜に浸透し、本質的に高い細胞透過性を有していることになる。重要なことに、CNAが細胞に侵入する能力は、CNA単量体の親油性を化学的に調整することによって最適化することができる。この能力は、インビボにおける安定性、並びに相補的なRNAおよびDNAに対するCNAの高い親和性および特異性と組み合わされて、RNAおよび/またはDNA干渉に利用される。具体的には、CNAは標的遺伝子および経路全体を抑制するために使用される。この使用は、治療剤および遺伝子制御を含む機構研究に広範囲な影響を与える。さらに、この細胞透過能は、外来性色素または治療用分子(例えば、タンパク質)の送達に有用である。
開示のCNA重合体は、細胞または対象にインビボ投与することができる。概して、本組成物は、対象とする用途に適した医薬組成物として調製されることが望ましい。従って、本明細書で上記のCNAを含有する薬剤または医薬組成物を作製する方法が含まれる。典型的に、医薬組成物(薬剤)の調製には、発熱物質、並びにヒトまたは動物に有害であり得る他のいかなる不純物も本質的に含まない医薬組成物を調製することが必要とされる。典型的に、本医薬組成物は、組成物の成分を安定させ、標的細胞(例えば、腫瘍細胞)による取り込みを可能にするために、適切な塩および緩衝液を含有する。
本開示は、一つまたは複数の容器中の本開示の一つまたは複数のCNA分子を含むキットも提供する。いくつかの例では、CNA分子は凍結乾燥されており、対象への投与または他の何らかの使用の前に、再構成される。キットは、他の薬剤、例えば薬学的に許容できる担体、説明書等を所望により含むことができる。
CNA設計:CNA単量体の設計は、ペプチド核酸(PNA)のDNA模倣体としての利用の成功に触発されたものである。最初のPNAはアミノエチルグリシン(AEG)骨格を用いて合成されたが、これは、DNAのリン酸塩−リボース骨格のそれに類似した反復単位の距離および最適化された結合角を示した初期の分子モデリングに基づいて選択されたものである。その発見から、PNAのいくつかの変種が合成および評価されており、ハイブリダイゼーションに必要とされる基本的な構造的制約が明らかにされている。最も決定的な制約は、鎖の骨格に沿った側鎖核酸塩基間の距離であり、最適な距離は6個の原子である。ssDNAとのハイブリダイゼーションが、核酸塩基間に5原子または7原子のスペーサーを有するPNAについて観察されているが、6原子のスペーサーを有するPNA骨格変種が、それらのより高い融解温度によって示されるように、より大きな安定性を示す。
DNA SNPのCNAオリゴマー検出の実証
DNAオリゴヌクレオチドアレイは、固体基板に固定された様々なDNA配列のスポットから成り、これにより、遺伝物質の試料との相補的ハイブリダイゼーション事象の評価が可能になる。この技術は、ゲノム配列決定、病原体ゲノム解析、および遺伝子発現解析等の種々の遺伝子スクリーニング応用で利用されている。CNAは、SNP検出のための診断用DNAアレイを作製するための簡易な方法を可能にする。巨大な核酸塩基重合体を合成する経路を与えることに加え、チオール−エン化学作用は容易に光誘導され、反応に正確な時間空間的制御をもたらす。チップ上のCNAアレイの作製は、レーザーまたは光の遮蔽を用いて配列特異的な伸長を方向づけることにより、達成される。実証実験として、蛍光標識したDNAを購入し、CNAマイクロアレイが特異的な配列を捕捉する能力を評価する。特定の例では、CNAマイクロアレイの、癌診断に一般的に使用されるジェネティックバイオマーカーであるKRAS癌遺伝におけるSNP(コドン12におけるC−>G)を検出する効率が評価される。
チオエーテル核酸による表面の修飾
開示のCNA分子が相補DNAに対してより良好な親和性を有することの簡単な実証として、表面修飾にCNA配列を組み込んだ。この感度の増加により、CNA分子は、表面上でのDNA鎖検出のための高感度プローブとなる。この試験において、最初のステップは、CNA(ポリT)鎖およびDNA(ポリA)鎖の両方を、同じ添加量(1μM)でスライドガラス上に付着させることであった(図18参照)。過剰な蛍光相補DNA鎖を、スライドガラス上のDNAおよびCNAを検出するための蛍光プローブとして使用した。図19に示されるように、この試験の結果は、CNAがDNAよりも多い蛍光強度を有することを示している。このデータは、CNA分子が、DNAそれ自体よりも相補DNA鎖に対してより感度が高いことを示している。
ヒドロゲルへのクリック核酸の組込み
CNA−DNAハイブリッドをヒドロゲル形成における架橋剤として導入した。この試験において、4腕のPEG−ポリA(DNA)および2腕のPEGポリT(CNA)を、PEG−アクリレートとのチオール−マイケル付加を用いて合成した。これら2つの基質を緩衝液中で混合し(5〜8重量%)、ヒドロゲルの形成を観察した。これらの結果は、例えば生体適合性ヒドロゲルにおける、分子構成単位としての、開示のCNA分子の弾力性を示している。
Claims (38)
- 所望により保護されたチオールと、
所望により保護されたチオール−クリック受容体と、
所望により保護された核酸塩基(NB)と、
3以上の結合価を有する原子を含む骨格と、を含み、
前記所望により保護されたチオール、所望により保護されたチオール−クリック受容体部分および所望により保護された核酸塩基は、独立して前記骨格に共有結合により連結されている、
クリック核酸単量体。 - 前記クリック核酸の骨格が、3の結合価を有する一つまたは複数の追加の原子を含む、請求項1または2に記載のクリック核酸単量体。
- 核酸塩基側鎖がリンカーを含み、前記リンカーが前記核酸塩基を3以上の結合価を有する原子に共有結合により連結させる、請求項1〜7のいずれか一項に記載のクリック核酸単量体。
- 前記リンカーが−C(O)C−を含む、請求項8に記載のクリック核酸単量体。
- 前記所望により保護されたチオール−クリック受容体が、ビニル、ビニルエーテル、アリルエーテル、ノルボルネン、ビニルスルホン、エポキシ、アクリレート、イソシアネート、アルキン、メタクリレート、マレイミド、ハロゲン化物またはそのアルキル伸長物を含む、請求項1〜9のいずれか一項に記載のクリック核酸単量体。
- 前記ビニル部分が以下の構造:
−CR5=CR6R7、
を有し、
式中、R5、R6、およびR7は、独立して水素、ヒドロカルビル、置換ヒドロカルビル、置換ヘテロシクロ、アルキル、置換アルキル、アシル、−C(O)R、−C(O)OR、または−C(O)NRaRb、アリールもしくは置換アリールまたは複素環である、請求項10に記載のクリック核酸単量体。 - 3以上の結合価を有する前記原子が窒素(N)または炭素(C)である、請求項1〜11のいずれか一項に記載のクリック核酸単量体。
- 前記単量体が、前記チオール部分および前記所望により保護されたチオール−クリック受容体の末端炭素を含む5〜9原子の反復単位を有する、請求項1〜12のいずれか一項に記載のクリック核酸単量体。
- 前記単量体が、前記チオール部分および前記所望により保護されたチオール−クリック受容体の末端炭素を含む6原子の反復単位を有する、請求項1〜13のいずれか一項に記載のクリック核酸単量体。
- 前記チオール部分が保護されている、請求項1〜14のいずれか一項に記載のクリック核酸単量体。
- 前記チオール−クリック受容体が保護されている、請求項1〜15のいずれか一項に記載のクリック核酸単量体。
- 前記核酸塩基が保護されている、請求項1〜16のいずれか一項に記載のクリック核酸単量体。
- 前記所望により保護されたチオール−クリック受容体が、所望により置換されたビニル、ビニルエーテル、アリルエーテル、ノルボルネン、イソシアネート、ビニルスルホン、エポキシ、アクリレート、メタクリレート、マレイミド、ハロゲン化物およびそれらのアルキル伸長物である、請求項1〜20のいずれか一項に記載のクリック核酸単量体。
- 前記単量体がN−ビニルチオールアセトアミド(VTA)骨格を含む、請求項1〜22のいずれか一項に記載のクリック核酸単量体。
- 前記単量体がN−ビニルチオールエチルアミン(VTE)骨格を含む、請求項1〜22のいずれか一項に記載のクリック核酸単量体。
- 前記単量体がA、G、T、U、またはC核酸塩基を含む、請求項1〜24のいずれか一項に記載のクリック核酸単量体。
- 前記単量体が図4、5、7〜14または18のいずれか一つに示されるクリック核酸を含む、請求項1〜25のいずれか一項に記載のクリック核酸単量体。
- チオールとチオール−クリック受容体との反応を介して、請求項1〜26のいずれか1項に記載のクリック核酸単量体が請求項1〜26のいずれか1項に記載のもう1つのクリック核酸単量体に共有結合により連結されたものを含む、クリック核酸重合体。
- 前記クリック核酸重合体がエフェクター分子に共有結合している、請求項27に記載のクリック核酸重合体。
- 前記エフェクター分子が検出可能なマーカーである、請求項28に記載のクリック核酸重合体。
- 前記エフェクター分子が生物活性化合物である、請求項28に記載のクリック核酸重合体。
- 前記チオ−エーテル重合体が表面に結合している、請求項27〜30のいずれか一項に記載のクリック核酸重合体。
- 請求項27〜31のいずれか一項に記載のクリック核酸重合体を含む、アレイ。
- 請求項27〜30のいずれか1項に記載のクリック可能な核酸重合体を含む、組成物。
- 生理学的に許容できる担体をさらに含む、請求項32に記載の組成物。
- クリック核酸単量体を作製する方法であって、図5、8および/または15に示されるスキームを含む、方法。
- 前記クリック核酸単量体が請求項1〜27のいずれか一項に記載の前記クリック核酸単量体を含む、請求項35に記載の方法。
- クリック核酸重合体を作製する方法であって、図2、9、または15に示されるスキームを含む、方法。
- 請求項27〜31のいずれか一項に記載の前記クリック核酸重合体の使用。
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