JP2022500442A - Dnaとのタンパク質重合のプログラミング - Google Patents
Dnaとのタンパク質重合のプログラミング Download PDFInfo
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- JP2022500442A JP2022500442A JP2021514129A JP2021514129A JP2022500442A JP 2022500442 A JP2022500442 A JP 2022500442A JP 2021514129 A JP2021514129 A JP 2021514129A JP 2021514129 A JP2021514129 A JP 2021514129A JP 2022500442 A JP2022500442 A JP 2022500442A
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- C08H—DERIVATIVES OF NATURAL MACROMOLECULAR COMPOUNDS
- C08H1/00—Macromolecular products derived from proteins
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L89/00—Compositions of proteins; Compositions of derivatives thereof
Abstract
Description
本出願は、2018年9月14日に出願された米国仮特許出願第62/731,601号および2018年9月14日に出願された米国仮特許出願第62/731,735号の米国特許法第119条(e)下の優先権の利益を主張し、それらの各々は参照によりそれらの全体が本明細書に組み込まれる。
本発明は、海軍研究局(Office of Naval Research)によって授与された認可番号N00014−15−1−0043の下で政府の支援を受けてなされた。政府は、本発明における特定の権利を有する。
本開示の一部である配列表を明細書と同時にテキストファイルとして提出する。配列表を含むテキストファイルの名称は、「2018−151R_Seqlisting.txt」であり、これは2019年9月13日に作成され、サイズは1,521バイトである。配列表の内容は、参照により本明細書に組み込まれる。
・多段階触媒作用
・組み立てライン(assembly−line)生合成
・組織工学
・タンパク質組成によって決定される特有のバルク物性を有する軟質材料
・任意のタンパク質をポリマー構造に組み込むことができる一般化可能な戦略
・調整可能な分子量分布および構造を有するタンパク質ポリマー材料
・オリゴヌクレオチド長は、特定のタンパク質間距離を定義するように調整することができる。
本明細書で使用される「タンパク質」は、一連のアミノ酸を含む任意の部分を含む。いくつかの実施形態では、本開示のタンパク質ポリマーは、状態の治療または診断のために患者に投与され得る。この用語にはペプチドも含まれる。本明細書で使用される「タンパク質モノマー」は、オリゴヌクレオチドが結合しており、かつ、本明細書に記載の方法に従って重合を受けることができる、任意のタンパク質を指す。
いくつかの態様では、本開示は、マルチブロックタンパク質ポリマーを作製する方法を提供する。かかる方法は、本明細書に開示されるタンパク質ポリマーの「リビング」特性を利用する。本開示の方法は、例えば反応に新鮮なタンパク質モノマーを添加することにより、成長し続けることができるタンパク質ポリマーを提供する。したがって、様々な実施形態では、タンパク質ポリマーは、任意の組み合わせで合成されてもよく、複数の異なるタンパク質由来の部分を組み合わせてタンパク質ポリマーにすることができる。したがって、いくつかの実施形態では、本開示は、様々なタンパク質由来の部分が、各部分によって提供される特性を示す単一のタンパク質ポリマー(すなわち、ヘテロマータンパク質ポリマー)に組み立てられることを企図する。あるいは、タンパク質ポリマーは、ホモポリマーとして合成されてもよく、タンパク質ポリマーを合成するために使用される各タンパク質モノマーのタンパク質部分は同じである。
本明細書で使用される「ヌクレオチド」という用語またはその複数形は、本明細書で論じられ、さもなければ当技術分野で知られている変形形態と交換可能である。ある特定の例では、当技術分野では、天然に存在するヌクレオチド、および修飾ヌクレオチドを含む天然に存在しないヌクレオチドを包含する「核酸塩基」という用語を使用する。したがって、ヌクレオチドまたは核酸塩基は、天然に存在する核酸塩基A、G、C、T、およびUを意味する。天然に存在しない核酸塩基には、例えばおよび限定するものではないが、キサンチン、ジアミノプリン、8−オキソ−N6−メチルアデニン、7−デアザキサンチン、7−デアザグアニン、N4,N4−エタノシトシン、N’,N’−エタノ−2,6−ジアミノプリン、5−メチルシトシン(mC)、5−(C3−C6)−アルキニル−シトシン、5−フルオロウラシル、5−ブロモウラシル、プソイドイソシトシン、2−ヒドロキシ−5−メチル−4−トリアゾロピリジン、イソシトシン、イソグアニン、イノシン、ならびにBennerらの米国特許第5,432,272号およびSusan M.Freier and Karl−Heinz Altmann,1997,Nucleic Acids Research,vol.25:pp 4429−4443に記載の「天然に存在しない」核酸塩基が含まれる。「核酸塩基」という用語には、既知のプリンおよびピリミジン複素環だけでなく、その複素環類似体および互変異性体も含まれる。さらに、天然に存在するおよび天然に存在しない核酸塩基には、米国特許第3,687,808号(Merigan,et al.)、Sanghviによる第15章、Antisense Research and Application,Ed.S.T.Crooke and B.Lebleu,CRC Press,1993、Englisch et al.,1991,Angewandte Chemie,International Edition,30:613−722(特に第622頁および第623頁を参照のこと)、ならびにConcise Encyclopedia of Polymer Science and Engineering,J.I.Kroschwitz Ed.,John Wiley&Sons,1990,pages 858−859,Cook,Anti−Cancer Drug Design 1991,6,585−607が含まれ、これらの各々は、参照によりそれらの全体が本明細書に組み込まれる。様々な態様では、オリゴヌクレオチドはまた、最も古典的な意味でのヌクレオシド塩基ではないがヌクレオシド塩基として機能する特定の「普遍的な塩基」を含む核酸塩基のように機能することができる、複素環式化合物などの化合物を含む天然に存在しないヌクレオチドのカテゴリーである1つ以上の「ヌクレオシド塩基」または「塩基単位」を含む。普遍的な塩基には、3−ニトロピロール、任意選択で置換されたインドール(例えば、5−ニトロインドール)、および任意選択で置換されたヒポキサンチンが含まれる。他の望ましい普遍的な塩基には、ピロール、ジアゾール、またはトリアゾール誘導体が含まれ、当技術分野で知られている普遍的な塩基が含まれる。
いくつかの態様では、本開示は、本開示のタンパク質ポリマーを対象に投与することを含む、治療を必要とする対象を治療する方法を提供する。
タンパク質−DNAモノマーの合成および特性評価。GFPを細菌発現システムで発現し、Ni−NTAアフィニティーを使用して精製した。Glen Researchから購入した試薬を用いた標準的な固相プロトコルを使用して、DNAを合成した。以下の配列を使用した:
タンパク質は、生物システムの中心的なビルディングブロックであり、明確に規定された構造および洗練された化学機能により、超分子材料の強力なシントンである。自然界における明確に規定された1、2、および3次元機能構造へのそれらの組み立ては、タンパク質の設計構造への組み立てを画策する努力を刺激している[Pieters et al.,J.,Natural supramolecular protein assemblies.Chem.Soc.Rev.2016,45 (1),24−39;Mann,Angew.Chem.Int.Ed.2008,47(29),5306−5320]。しかしながら、タンパク質の組み立ては、その表面の化学的不均一性のために、合成的に制御することは困難であり、この目標に向けた大きな課題を表している[Papapostolou et al.,Mol.Biosyst.2009,5(7),723−732]。この課題に対処するために、本実施例では、タンパク質の組み立てを媒介し、タンパク質の表面上のDNA修飾が組み立ての結果を制御するように設計され得る方法についての基本的な理解するために、堅牢かつプログラム可能なDNA相互作用の使用を調べた[Jones et al.,Science 2015,347(6224)]。
本明細書に記載されるように、本開示の態様のいずれかでは、タンパク質の会合経路を制御するためにオリゴヌクレオチドを利用する方法が提供される。いくつかの態様では、方法は、重合に対するエネルギー障壁をプログラムするための配列特異的オリゴヌクレオチド相互作用の使用を含み、これにより、段階成長または鎖成長経路のいずれかにアクセスすることが可能なる。単一のDNA修飾を有する変異緑色蛍光タンパク質(mGFP)−DNAモノマーの2つのセットを合成し、特性評価した。付加されたDNAの意図的に制御された配列およびコンフォメーションに応じて、これらのモノマーは、段階成長または鎖成長経路のいずれかを通して重合することができる。Volta位相板技術を使用した低温電子顕微鏡法により、オリゴマーおよびポリマー生成物、さらに、小さなmGFP−DNAモノマーの分布を視覚化することができる。段階成長DNA設計では環状および線状ポリマー分布が観察されたが、鎖成長システムの場合では、線状鎖が専ら観察され、鎖長が開始剤鎖の濃度に依存することが認められた。重要なことに、鎖成長システムは、リビング特性を有しており、それにより、新鮮なモノマーを付加することで鎖を伸長することができる。本研究は、タンパク質組み立てに対する機械的制御の重要かつ初期の例を表し、それにより、構造に対する優れた制御を有する、オリゴマーおよびポリマータンパク質ベース材料を合成するための堅牢な方法論を確立する。
mGFPの発現および精製。前述した変異EGFP(mGFP)の遺伝子を含有する変異プラスミドを、熱ショックによりOneShot(登録商標)BL21(DE3)Chemically Competent E.coli(Thermo Fisher)に形質転換し、細胞を100μg/ mLアンピシリンを有するLB寒天プレート上で一晩増殖させた。単一のコロニーを選び、7mLの培養物を100μg/mLアンピシリンを含むLBブロス[Hayes et al.,J.Am.Chem.Soc.2018,140(29),9269−9274]中で37℃で一晩増殖させた。これらの培養物を、1%グリセロールおよび100μg/mLアンピシリンを含む、1LのTerrific Broth(Thermo Fisher)に添加し、細胞を37℃で光学密度0.6まで増殖させ、次いで、0.02 wt%アラビノースで17℃で一晩誘導した。細胞を沈降させ(6000g、30分間)、100mLの1xPBSに再懸濁し、次いで高圧ホモジナイザーを使用して溶解した。細胞溶解物を30000gで30分間遠心分離することにより清澄化し、Bio−Scale(商標)MiniProfinity(商標)IMACカートリッジ(Bio−Rad)に充填した。カラムを100mLの再懸濁緩衝液で洗浄し、次いで250mMイミダゾールを含む同じ緩衝液で溶出した。Macrp−Prep(登録商標)DEAE樹脂に充填し、20mLの1xPBSで洗浄することにより、溶出した画分をさらに精製した。mGFPを1xPBS+0.25M NaClの溶液で溶出した。
ポリマー組み立て条件。研究されたすべてのmGFP−DNAポリマーは、1xPBS+0.5M NaCl中の1μMの各ビルディングブロック(2μMの総タンパク質濃度)で室温で組み立てられた。提示するすべての特性評価データのために、試料を室温で分析前に最低12時間インキュベートした。鎖成長システムでは、開始剤鎖を添加する前に、両方のモノマーを合わせて溶液中で混合した。このシステムでは、報告する開始剤の当量は、単一のビルディングブロックに対する当量を指す(例えば、0.4当量の開始剤では、試料は、0.4μM開始剤、1μM HA、および1μM HBを含有する)。
試料の凍および画像化。試料溶液を400メッシュの1.2/1.3 C−Flatグリッド(Protochips)に堆積させ、Vitrobot(商標)MarkIVを使用して液体エタンに急速凍結した。Volta位相板およびOmegaエネルギーフィルターを備えた300kVで作動するJEOL3200FS顕微鏡を使用して、グリッドを画像化した。取得した画像において90°の位相シフトが得られるように、顕微鏡を整列し、調整した。動画は、1.1オングストロームのピクセルサイズのカウントモードを使用して、0.1〜1.0μmのデフォーカス範囲において、K2サミットカメラ(Gatan)で取得した。使用された線量率は、約10e−/pix/秒(試料の平面上で8.3e−/Å2/秒に相当する)であり、6秒間の総露光であった。
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Claims (41)
- タンパク質ポリマーを作製する方法であって、
(a)第1のオリゴヌクレオチドが結合している第1のタンパク質を含む第1のタンパク質モノマーであって、前記第1のオリゴヌクレオチドが、第1のドメイン(V)および第2のドメイン(W)を含む、第1のタンパク質モノマーと、
(b)第2のオリゴヌクレオチドが結合している第2のタンパク質を含む第2のタンパク質モノマーであって、前記第2のオリゴヌクレオチドが、第1のドメイン(V’)および第2のドメイン(W’)を含む、第2のタンパク質モノマーとを接触させることを含み、
(i)Vは、適切な条件下でハイブリダイズするためにV’に十分に相補的であり、(ii)Wは、適切な条件下でハイブリダイズするためにW’に十分に相補的であり、前記接触により、V’がVにハイブリダイズされ、
それにより、前記タンパク質ポリマーを作製する、方法。 - 前記接触により、WがW’にハイブリダイズすることが可能となる、請求項1に記載の方法。
- 前記第1のタンパク質および前記第2のタンパク質が同じである、請求項1または2に記載の方法。
- 前記第1のタンパク質および前記第2のタンパク質が異なる、請求項1または2に記載の方法。
- 前記第1のタンパク質および前記第2のタンパク質が、マルチマータンパク質のサブユニットである、請求項1〜4のいずれか一項に記載の方法。
- 前記第1のオリゴヌクレオチドが、前記第1のタンパク質の表面上のリジンまたはシステインを介して前記第1のタンパク質に結合している、請求項1〜5のいずれか一項に記載の方法。
- 前記第1のオリゴヌクレオチドが、DNA、RNA、それらの組み合わせ、またはそれらの修飾体である、請求項1〜6のいずれか一項に記載の方法。
- Vが、約10〜100ヌクレオチド長である、請求項1〜7のいずれか一項に記載の方法。
- Wが、約10〜100ヌクレオチド長である、請求項1〜8のいずれか一項に記載の方法。
- 前記第2のオリゴヌクレオチドが、前記第2のタンパク質の表面上のリジンまたはシステインを介して前記第2のタンパク質に結合している、請求項1〜9のいずれか一項に記載の方法。
- 前記第2のオリゴヌクレオチドが、DNA、RNA、それらの組み合わせ、またはそれらの修飾体である、請求項1〜10のいずれか一項に記載の方法。
- V’が、約10〜100ヌクレオチド長である、請求項1〜11のいずれか一項に記載の方法。
- W’が、約10〜100ヌクレオチド長である、請求項1〜12のいずれか一項に記載の方法。
- 前記タンパク質ポリマーが、ヒドロゲルまたは治療剤である、請求項1〜13のいずれか一項に記載の方法。
- 前記治療剤が、抗体、細胞透過性ペプチド、ウイルスキャプシド、天然変性タンパク質、レクチン、または膜タンパク質である、請求項14に記載の方法。
- タンパク質ポリマーを作製する方法であって、
(a)第1のオリゴヌクレオチドが結合している第1のタンパク質を含む第1のタンパク質モノマーであって、前記第1のオリゴヌクレオチドは、第1のドメイン(X)、第2のドメイン(Y’)、第3のドメイン(Z)、および第4のドメイン(Y)を含み、Yは、適切な条件下でハイブリダイズして、第1のヘアピン構造を生成するためにY’に十分に相補的である、第1のタンパク質モノマーと、
(b)第2のオリゴヌクレオチドが結合している第2のタンパク質を含む第2のタンパク質モノマーであって、前記第2のオリゴヌクレオチドは、第1のドメイン(Y)、第2のドメイン(X’)、第3のドメイン(Y’)、および第4のドメイン(Z’)を含み、Yは、適切な条件下でハイブリダイズして、第2のヘアピン構造を生成するためにY’に十分に相補的である、第2のタンパク質モノマーと、
(c)第1のドメイン(Y)および第2のドメイン(X’)を含む開始剤オリゴヌクレオチドとを接触させることを含み、
前記接触により、(i)前記開始剤オリゴヌクレオチドのX’が、前記第1のオリゴヌクレオチドのXにハイブリダイズし、前記開始剤オリゴヌクレオチドのYが、前記第1のオリゴヌクレオチドのYと置き換わり、それにより、前記第1のヘアピン構造を開き、(ii)前記第2のオリゴヌクレオチドのZ’が、前記第1のオリゴヌクレオチドのZにハイブリダイズし、それにより、前記第2のヘアピン構造を開き、
それにより、前記タンパク質ポリマーを作製する、方法。 - 前記第1のタンパク質および前記第2のタンパク質が同じである、請求項16に記載の方法。
- 前記第1のタンパク質および前記第2のタンパク質が異なる、請求項16に記載の方法。
- 前記第1のタンパク質および前記第2のタンパク質が、マルチマータンパク質のサブユニットである、請求項16〜18のいずれか一項に記載の方法。
- 前記第1のオリゴヌクレオチドが、前記第1のタンパク質の表面上のリジンまたはシステインを介して前記第1のタンパク質に結合している、請求項16〜19のいずれか一項に記載の方法。
- 前記第1のオリゴヌクレオチドが、DNA、RNA、それらの組み合わせ、またはそれらの修飾体である、請求項16〜19のいずれか一項に記載の方法。
- 前記第1のオリゴヌクレオチドのXが、約2〜20ヌクレオチド長である、請求項16〜21のいずれか一項に記載の方法。
- 前記第1のオリゴヌクレオチドのY’が、約12〜80ヌクレオチド長である、請求項16〜22のいずれか一項に記載の方法。
- 前記第1のオリゴヌクレオチドのZが、約2〜20ヌクレオチド長である、請求項16〜23のいずれか一項に記載の方法。
- 前記第1のオリゴヌクレオチドのYが、約12〜80ヌクレオチド長である、請求項16〜24のいずれか一項に記載の方法。
- 前記第2のオリゴヌクレオチドが、前記第2のタンパク質の表面上のリジンまたはシステインを介して前記第2のタンパク質に結合している、請求項16〜25のいずれか一項に記載の方法。
- 前記第2のオリゴヌクレオチドが、DNA、RNA、それらの組み合わせ、またはそれらの修飾体である、請求項16〜26のいずれか一項に記載の方法。
- 前記第2のオリゴヌクレオチドのYが、約12〜80ヌクレオチド長である、請求項16〜27のいずれか一項に記載の方法。
- 前記第2のオリゴヌクレオチドのX’が、約2〜20ヌクレオチド長である、請求項16〜28のいずれか一項に記載の方法。
- 前記第2のポリヌクレオチドのY’が、約12〜80ヌクレオチド長である、請求項16〜29のいずれか一項に記載の方法。
- 前記第2のポリヌクレオチドのZ’が、約2〜20ヌクレオチド長である、請求項16〜30のいずれか一項に記載の方法。
- 前記タンパク質ポリマーが、ヒドロゲルまたは治療剤である、請求項16〜31のいずれか一項に記載の方法。
- 前記治療剤が、抗体、細胞透過性ペプチド、ウイルスキャプシド、天然変性タンパク質、レクチン、または膜タンパク質である、請求項32に記載の方法。
- 第3のオリゴヌクレオチドが結合している第3のタンパク質を含む第3のタンパク質モノマーを付加することをさらに含み、前記第3のオリゴヌクレオチドが、第1のドメイン(X)、第2のドメイン(Y’)、第3のドメイン(Z)、および第4のドメイン(Y)を含み、Yが、適切な条件下でハイブリダイズして、第3のヘアピン構造を生成するためにY’に十分に相補的である、請求項16〜33のいずれか一項に記載の方法。
- 前記第3のタンパク質が、前記第1のタンパク質と同じである、請求項34に記載の方法。
- 前記第3のタンパク質が、前記第2のタンパク質と同じである、請求項34に記載の方法。
- 第4のオリゴヌクレオチドが結合している第4のタンパク質を含む第4のタンパク質モノマーを付加することをさらに含み、前記第4のオリゴヌクレオチドが、第1のドメイン(Y)、第2のドメイン(X’)、第3のドメイン(Y’)、および第4のドメイン(Z’)を含み、Yは、適切な条件下でハイブリダイズして、第4のヘアピン構造を生成するためにY’に十分に相補的である、請求項16〜36のいずれか一項に記載の方法。
- 前記第4のタンパク質が、前記第1のタンパク質と同じである、請求項37に記載の方法。
- 前記第4のタンパク質が、前記第2のタンパク質と同じである、請求項37に記載の方法。
- 治療を必要とする対象を治療する方法であって、請求項1〜39のいずれか一項に記載のタンパク質ポリマーを前記対象に投与することを含む、方法。
- 請求項1〜39のいずれか一項に記載のタンパク質ポリマーおよび生理学的に許容される担体を含む、組成物。
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WO2020056341A2 (en) | 2020-03-19 |
US20220056220A1 (en) | 2022-02-24 |
SG11202102531WA (en) | 2021-04-29 |
EP3849584A2 (en) | 2021-07-21 |
CN112912422A (zh) | 2021-06-04 |
WO2020056341A3 (en) | 2020-04-16 |
AU2019339509A1 (en) | 2021-05-13 |
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EP3849584A4 (en) | 2022-06-22 |
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