JP2006219435A - 細胞透過性ペプチド - Google Patents
細胞透過性ペプチド Download PDFInfo
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- JP2006219435A JP2006219435A JP2005035290A JP2005035290A JP2006219435A JP 2006219435 A JP2006219435 A JP 2006219435A JP 2005035290 A JP2005035290 A JP 2005035290A JP 2005035290 A JP2005035290 A JP 2005035290A JP 2006219435 A JP2006219435 A JP 2006219435A
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Abstract
【解決手段】 1億種以上もの多様性を有するランダムペプチドライブラリの中から、ファージ表面提示法を使用して、細胞に結合する/あるいは細胞内へ侵入する能力を有するペプチドを選択濃縮して数を絞込み、次いで、これら選択濃縮したペプチドと単独では細胞内に侵入することが出来ないタンパク質合成阻害因子(PSIF)との融合体を細胞に添加して、蛋白質合成阻害を指標とした細胞質移行性の評価を行う。
【選択図】 図1
Description
項1. 配列番号1〜16からなる群から選ばれる少なくとも1種のペプチド。
項2. 配列番号1、5、6、7、9、10、11、15および16からなる群から選ばれる少なくとも1種である、上記項1に記載のペプチド。
項3. 少なくとも1つのCys残基を前記アミノ酸配列のN末端及び/又はC末端に付加してなる上記項1又は2に記載のペプチド。
項4. 上記項1〜3のいずれかに記載のペプチドと生理活性物質とを直接的にまたは架橋剤を介して間接的に連結してなるペプチドコンジュゲート。
項5. 上記項1〜3のいずれかに記載のペプチド又は上記項4に記載のペプチドコンジュゲートを含むワクチン。
項6. 上記項1〜3のいずれかに記載のペプチド又は上記項4に記載のペプチドコンジュゲートを含む経皮吸収用製剤。
項7. 生理活性物質を細胞内に導入するための上記項1〜3のいずれかに記載のペプチドの使用。
ファージ表面提示:
18個のアミノ酸をランダムに並べた「ランダム18a.a.ペプチドライブラリ」と、配列GRKKRRQRRRPPQ(配列番号17)を有するTATペプチド(Tat 48-60)のうち、αへリックスの基点である3つのアミノ酸(即ち、第1番目のG、第7番目のQ、および第11番目のP)を固定してその他のアミノ酸を置換した「TATペプチドライブラリ」を作製した。20種類のアミノ酸をコードし得るNNS配列を導入したプライマーを用いてPCRを行い、PCR断片をファージミドベクターに組み込んだ。このベクターを大腸菌TG1に導入し、ヘルパーファージを感染させることで、多様な種類のペプチドを、ファージマイナー外殻蛋白質であるg3pの先端に発現するファージライブラリを作製した。ライブラリから任意にピックアップしたクローンのDNAシークエンスを解析した結果、独立したクローンで構成されていることを確認した。ファージ表面提示法は当業者に公知の方法である(図1参照)。
本発明によれば、TATペプチド(Tat48-60)よりも高い細胞透過性を有するペプチドが提供される。
本発明のペプチドに結合させる生理活性物質は、特に限定されないが、例えば、核酸、ペプチド、ポリペプチド、蛋白質、多糖および糖蛋白質からなる群から選択される。生理活性物質は、本発明ペプチドのどの部分に結合させても構わないが、C末端またはN末端、特にC末端に結合させるとリコンビナントの作製が容易であるので好ましい。
本発明の粘着テープ製剤は、例えば、上記の粘着性親水性ポリマーと親水性低分子物質を含有する水溶液または水/アルコール混合溶液に、防御抗原を必要な濃度で含むように調整された水分散液または水/アルコール混合分散液を加えてよく混合分散させた後、柔軟なシート状の支持体上に一定の厚さで塗布し、10〜200℃の範囲の適当な温度で乾燥することによって製造される。この時乾燥温度は、塗布した粘稠な分散液中の内容物の変質を防ぐためにはできるだけ低い温度が好ましく、通常30〜100℃の温度の範囲が用いられる。この方法で製造される粘着テープ製剤の粘着層は必要な濃度で、且つ均一に防御抗原を含有することになる。また、防御抗原の全体もしくは一部が、形成された粘着層に埋め込まれている形で存在しており、結果的に該防御抗原が適度に徐放されるように設計されることになる。また、本発明の粘着テープ製剤の別の製造方法としては、上記の粘着性親水性高分子と親水性低分子物質を含む水溶液または水/アルコール混合溶液をそのまま柔軟なシート状の支持体上に一定の厚さで塗布し、10〜200℃の範囲の適当な温度で乾燥させることによって、また必要に応じて架橋処理することによって、まず防御抗原を含有しない粘着テープを製造した後、防御抗原を必要な量で含むように調整された水分散液または水/アルコール混合分散液を、該粘着テープの粘着層表面に必要な防御抗原植種量になるように塗布し、水またはアルコールを蒸散乾燥させる方法が挙げられる。防御抗原を含む粘着層領域と、防御抗原を含まない粘着層領域を有する剤型の粘着テープ製剤は、上記2通りの製造方法を適当に組み合わせることにより製造することができる。
ペプチドライブラリの作製
全20種類のアミノ酸がランダムに並んだ「ランダム18a.a.ペプチドライブラリ」、およびHIVのTat蛋白質に由来するTatペプチド(13mer;Tat48-60)の一部がランダムなアミノ酸に置換された「TATペプチドライブラリ」を作製するため、PCR法を用い、全20種類のアミノ酸をコードするランダムな塩基配列(NNS配列;N=A/T/G/C、S=G/C)がアミノ酸18個分並んだ遺伝子ライブラリと、Tatペプチドの塩基コドンの一部がNNS配列に置換された遺伝子ライブラリを調製した。
得られたコロニーから任意に選択した各クローンのプラスミドをQIAprep(登録商標) Miniprep kit(QIAGEN)を用いて回収し、DNA sequencing Kit(Applied Biosystems)および5x Sequencing Buffer(Applied Biosystems)を用いてシークエンス反応を行った。その後、PERFORMA Gel Filtration Cartridge(Edge Bio Systems)を用いて精製し、減圧加熱により乾燥させた。シークエンス解析はABI PRISM 310(Applied Biosystems)により行った。
作製した2つのライブラリ遺伝子をそれぞれ組み込んだファージミドベクターpCANTAB5E(アマシャムバイオサイエンス社製)を大腸菌TG1にエレクトロポレーションし、その適量を50μg/mLアンピシリン、2%グルコース含有LBプレートに播種し、37℃で一晩培養した。50μg/mLアンピシリン、2%グルコース含有2YT培地を加えてコロニーをすべて回収し、250rpm 37℃でOD600=0.3まで培養した。M13KO7ヘルパーファージ(Invitrogen TM life technologies)を添加し、110rpm 37℃で30分間、250rpm 37℃で30分間培養した後、2,000rpmで10分間遠心し、得られたペレットに対して50μg/mLアンピシリン、100μg/mLカナマイシン(Sigma-Aldrich,Inc.)含有2YT培地を添加して6時間培養することで、ペプチドを表面提示したファージを調整した。
ファージ粒子を含むTG1培養液を4℃ 2,000rpmで10分間遠心し、上清を回収した。さらに10,000rpmで15分間遠心し、回収した上清に氷冷した20% PEG-8,000(和光純薬株式会社)、2.5M NaCl(和光純薬株式会社)を1/5 volume加え、激しく混和して氷上で2〜3時間静置した。次いで15,000rpmで10分間遠心して得られたファージペレットをNTE Buffer(100mM NaCl、10mM Tris、1mM EDTA)に懸濁し、0.45μmのMillex(登録商標)-HV(MILLIPORE)を用いてフィルターろ過して精製ファージ溶液とした。
A431細胞(ヒト表皮細胞)を用いて各ライブラリについてパンニングを行った。6穴プレート(NUNCTM)にA431細胞を5.0x105cells/wellで播種し、37℃、飽和蒸気圧、5%炭酸ガス気相下で24時間培養した。PBSで3回洗浄した後、Opti-MEM(Invitrogen TM life technologies)で希釈した2%ウシ血清アルブミン(BSA)を用いて37℃で2時間ブロッキングした。精製したファージについても等量の2%BSAを用いて4℃で1時間ブロッキングした。ブロッキングが終了したファージをA431細胞に加え、15分ごとに振とうしながら37℃で2時間培養した。細胞をPBSで20回洗浄した後、50mM HCl 1mLを加えて4℃で10分間培養した。このファージ溶出液を回収し、1M Tris-HCl pH8.0 500μLを添加した後、その50μLを用いて下記の方法に従いタイターを測定した。残りのファージ溶液は2%グルコース含有2YT培地を4.5mL加えて再度TG1に感染させ、増幅させて上記のファージ作製法に準じてファージを産出し、再度同様のパンニング操作を行ったものを2nd、3rd、4thパンニングとした。
2%グルコース含有2YT培地でOD600=0.3まで培養したTG1に対して、10倍希釈で段階希釈したファージ溶液を添加し、37℃で1時間培養した。培養液の一部に50μg/mLアンピシリン、2%グルコース含有2YT培地を添加し、クロンディスクに播種し一晩培養した。各希釈段階でのコロニー数を計測することで、inputファージおよびoutputファージのタイターを算出した。
作製したライブラリ(input)および2nd、3rd、4thパンニング後のライブラリから回収したプラスミドをNcoI(東洋紡株式会社)およびNotIで処理した。あらかじめNcoIおよびNotIで処理したPSIF発現ベクターpY7(pCantab5eにPSIF発現コドンを組み込んだもの)にライゲーションキットVer.2(宝酒造株式会社)を用いて組み込むことで、ペプチドとPSIFとの融合体を発現するプラスミドを構築した。PSIF(蛋白質合成阻害因子)としては、ジフテリアトキシン(GenBank; A04646)もしくは緑膿菌菌体外毒素(GenBank; K01397)の蛋白質合成阻害活性領域などを利用した。
ペプチドとPSIFとの融合体を発現するプラスミドをTG1にエレクトロポレーションにより導入し、得られたコロニーを96穴プレート(NUNCTM)へランダムにピックアップして一晩培養した。50μg/mLアンピシリン、2%グルコース含有2YT培地100μLを新たに添加したプレートに、一晩培養した培養液10μLを添加し、OD600=0.4〜0.5まで培養した。3,000rpmで20分間遠心した後、上清を除き1mM IPTG(Sigma-Aldrich,Inc.)、50μg/mLアンピシリン含有2YT培地200μLを添加し、37℃で12時間培養した。再び3,000rpm 20分間遠心し、得られた上清を以降のスクリーニングに供した。
96穴プレートにOpti-MEM(Invitrogen TM life technologies)で1.0x104cells/wellに希釈したA431細胞を播種し、終濃度10μg/mLになるようにシクロヘキシミド(和光純薬株式会社)を添加した。次いで、上記の方法に従って作製した培養上清をそれぞれ5μLずつ加え、37℃、飽和蒸気圧、5%炭酸ガス気相下で24時間培養した。その後、5mg/mLのMTT(和光純薬株式会社)溶液を10μL/well加え、さらに37℃で4時間培養した。20% SDS(和光純薬株式会社 Osaka, Japan)/0.01N HClを100μL/well加えて暗所で4時間静置し、マイクロプレートリーダーで吸光度を測定し(Test wave length;595nm/Reference wave length;655nm)、ペプチドによって細胞内に導入されたPSIFによる細胞傷害性を指標にペプチドの細胞内移行能を評価した。ViabilityはTATペプチド(Tat 48-60)とPSIFとの融合体を含む培養上清を作用させた群を100%として算出した。
Claims (7)
- 配列番号1〜16からなる群から選ばれる少なくとも1種のペプチド。
- 配列番号1、5、6、7、9、10、11、15および16からなる群から選ばれる少なくとも1種である、請求項1に記載のペプチド。
- 少なくとも1つのCys残基を前記アミノ酸配列のN末端及び/又はC末端に付加してなる請求項1又は2に記載のペプチド。
- 請求項1〜3のいずれかに記載のペプチドと生理活性物質とを直接的にまたは架橋剤を介して間接的に連結してなるペプチドコンジュゲート。
- 請求項1〜3のいずれかに記載のペプチド又は請求項4に記載のペプチドコンジュゲートを含むワクチン。
- 請求項1〜3のいずれかに記載のペプチド又は請求項4に記載のペプチドコンジュゲートを含む経皮吸収用製剤。
- 生理活性物質を細胞内に導入するための請求項1〜3のいずれかに記載のペプチドの使用。
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US11/883,810 US7989588B2 (en) | 2005-02-10 | 2006-02-09 | Cell permeable peptide |
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WO2011148996A1 (ja) * | 2010-05-25 | 2011-12-01 | 国立大学法人熊本大学 | 物質導入用液体培地及び細胞内への物質導入方法 |
JP2014500867A (ja) * | 2010-11-09 | 2014-01-16 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 皮膚浸透性および細胞侵入性(space)ペプチドとその使用法 |
JPWO2018074558A1 (ja) * | 2016-10-23 | 2019-11-07 | デンカ株式会社 | 複合ポリペプチド単量体、細胞浸透機能を有する当該複合ポリペプチドの単量体の会合体、及び、当該会合体を有効成分とする皮下、皮内、経皮又は筋肉内投与用ノロウイルスコンポーネントワクチン |
JP7062595B2 (ja) | 2016-10-23 | 2022-05-06 | デンカ株式会社 | 複合ポリペプチド単量体、細胞浸透機能を有する当該複合ポリペプチドの単量体の会合体、及び、当該会合体を有効成分とする皮下、皮内、経皮又は筋肉内投与用ノロウイルスコンポーネントワクチン |
US11517616B2 (en) | 2016-10-23 | 2022-12-06 | Denka Company Limited | Composite polypeptide monomer, aggregate of said composite polypeptide monomer having cell penetration function, and norovirus component vaccine for subcutaneous, intradermal, percutaneous, or intramuscular administration and having said aggregate as effective component thereof |
JP2020504090A (ja) * | 2016-12-16 | 2020-02-06 | アヴィックスジェン・インコーポレイテッド | 細胞膜透過ペプチドおよびこれを含む細胞内伝達体 |
JP2021098730A (ja) * | 2016-12-16 | 2021-07-01 | アヴィックスジェン・インコーポレイテッド | 細胞膜透過ペプチドおよびこれを含む細胞内伝達体 |
US11208433B2 (en) | 2017-12-28 | 2021-12-28 | Avixgen Inc. | Peptide for inhibiting skin inflammation and composition for preventing or treating skin inflammation containing the same |
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US7989588B2 (en) | 2011-08-02 |
EP2177531A3 (en) | 2010-07-28 |
US20110045009A1 (en) | 2011-02-24 |
EP2177531B1 (en) | 2015-08-12 |
WO2006085583A1 (ja) | 2006-08-17 |
EP1849798B1 (en) | 2014-10-01 |
EP1849798A1 (en) | 2007-10-31 |
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JP4596391B2 (ja) | 2010-12-08 |
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