JP3058686B2 - キメラｄｎａ―ｒｎａ触媒活性配列 - Google Patents

キメラｄｎａ―ｒｎａ触媒活性配列

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Publication number
JP3058686B2
JP3058686B2 JP50884090A JP50884090A JP3058686B2 JP 3058686 B2 JP3058686 B2 JP 3058686B2 JP 50884090 A JP50884090 A JP 50884090A JP 50884090 A JP50884090 A JP 50884090A JP 3058686 B2 JP3058686 B2 JP 3058686B2
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Prior art keywords
rna
catalytically active
dna
sequence
base sequence
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JPH04502256A (ja
Inventor
ロッシ，ジョン・ジェイ
チャン，パイロジ
カプラン，ブルース・イー
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City of Hope
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City of Hope
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • 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
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B64—AIRCRAFT; AVIATION; COSMONAUTICS
    • B64D—EQUIPMENT FOR FITTING IN OR TO AIRCRAFT; FLIGHT SUITS; PARACHUTES; ARRANGEMENTS OR MOUNTING OF POWER PLANTS OR PROPULSION TRANSMISSIONS IN AIRCRAFT
    • B64D13/00—Arrangements or adaptations of air-treatment apparatus for aircraft crew or passengers, or freight space, or structural parts of the aircraft
    • B64D13/06—Arrangements or adaptations of air-treatment apparatus for aircraft crew or passengers, or freight space, or structural parts of the aircraft the air being conditioned
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • 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
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1131—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against viruses
    • C12N15/1132—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against viruses against retroviridae, e.g. HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/11—Antisense
    • C12N2310/111—Antisense spanning the whole gene, or a large part of it
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/12—Type of nucleic acid catalytic nucleic acids, e.g. ribozymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/12—Type of nucleic acid catalytic nucleic acids, e.g. ribozymes
    • C12N2310/121—Hammerhead
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/322—2'-R Modification

Description

【発明の詳細な説明】 発明の分野 本発明はDNA−RNA触媒活性分子に関する。特に本発明
は例えばHIV−１のRNA塩基配列を切断するのに効果的な
キメラDNA−RNA−DNA−RNA−DNA触媒活性分子に関す
る。
背景技術 リボザイムは多くのRNA自己消化反応に介在する構造R
NA分子である。違った二次構造をもつ２つの異なるトラ
ンス作用性リボザイム、“ハンマーヘッド”および“ヘ
アピン”が明らかにされている。オンコジーンアンドエ
イズ（1990）［引用］は次のように述べている： “他に可能な人工的なアプローチはリボヌクレオチド
の触媒活性中心およびデオキシヌクレオチドの周辺配列
を含んだキメラ分子の開発である。RNA触媒活性中心お
よびDNA周辺配列からなるキメラ触媒は著しい安定性を
持ちながら生物学的活性を保持していることもまた想像
される。” ペロー（perreault）ら,Nature,344:565−567（199
0）は、触媒活性を持ったある種のデオキシリボヌクレ
オチドとリボオリゴヌクレオチドとの混合物を記載して
いる。実際に治療に有用なRNA−DNA触媒活性分子はまだ
見つかっていない。
発明の要約 本発明はRNA塩基配列を切断するのに有効なキメラDNA
/RNA触媒活性分子を提供する。本発明は特にHIV−１のR
NA塩基配列を標的にして切断する２つの異なったキメラ
DNA−RNA−DNA−RNA−DNA活性触媒分子を提供する。こ
れらのキメラ分子はRNA触媒活性中心の周辺のDNA塩基配
列を含む。HIV−１の基質RNAとの相互作用はHIV−１のR
NAとDNA周辺配列との間のワトソン−クリックによる塩
基間の相補性により起こされる。触媒リボヌクレオチド
中心は期待された位置において基質HIV−１ RNAのホス
ホジエステル結合を切断する。
発明の一般的な説明 一般的には本発明の触媒活性分子はハンマーヘッドあ
るいはヘアピンリボザイムとして機能する。好ましい分
子は２つの知られているRNA触媒活性中心がそれぞれの
３′および５′末端においてDNA塩基配列を両側に配
し、該DNAの対応する５′および３′末端と結合してい
る構造からなる。従ってこれらの分子は式ＩおよびIIに
より表される： （式中、X,YおよびＺはDNA塩基配列部分であり、AAAG,C
AAAGおよびAGUAGUCは触媒RNA塩基配列部分である。） 周辺のＸおよびＺの各塩基配列部分は基質の切断部位
の付近の適当な位置において基質RNAとの間に塩基間の
相補結合を起こしうるものであればどのようなDNA塩基
配列でもよい。これらの周辺配列はホスホジエステル、
ホスホロチオエート、メチルホスホネート、メチルホス
フェートあるいは類似の成分であってよい。
Ｙは好ましくは式III: で示される塩基間の相補対にみられるように、RNA塩基
配列部分の触媒活性による基質の切断に必要な様式で自
己の内部に相補性結合を形成するDNA塩基配列であれば
どのようなものでもよい。
本発明の触媒活性分子はApplied Biosystemsあるいは
Milligenで製造されているような市販のDNA合成機によ
り周知の方法で合成される。例えば、前記ペローらの文
献を参照せよ。
ＸおよびＺの配列は細胞への侵入性、細胞内での標的
指向性および触媒の最終的安定性を高めるためにリガン
ドによってそれぞれの３′および５′の位置で置換され
得る。そのようなリガンドの非限定的な例示としては、
他のヌクレオチド、蛋白質、炭水化物、脂質、ステロイ
ドホルモン、およびコレステロールが含まれる。
本発明の触媒活性分子はリポソーム、欠損ウイルス粒
子、ウイルス頭部、および標準的なDNA/RNAトランスフ
ェクション法を含んだ、周知のおよび入手可能な送達剤
もしくは系により投与されるが、しかしこれらに限定さ
れるものではない。
図面の説明 第１図はHIV−１の塩基配列と相補対を形成した本発
明の触媒活性分子の一つを表す。分子のRNA部分は線で
囲まれている。
第２図は他のHIV−１の塩基配列と相補的な配列をも
つ本発明の触媒活性分子の二つめを表す。分子のRNA部
分は線で囲まれている。
第３図Ａは同等の全DNA分子と比較して第１図の触媒
活性分子のリボヌクレアーゼＡによる消化を表す。条件
は50mM Tris−HCL緩衝液（pH8.0）10μｌ中のオリゴヌ
クレオチドに２×SSC緩衝液中の市販されている（Sigm
a）膵臓リボヌクレアーゼ10ユニットを加えた。32Pで末
端ラベルされたDRDRDあるいはDNA分子を8M尿素を含んだ
15％ポリアクリルアミドゲルで電気泳動する前にRNase
をサンプルと10分間インキュベートした。ゲルを10分間
オートラジオグラフ処理して、被照射部分を現像した。
第３図Ｂはチャン（Chang）ら,Clinical Biotechnolo
gy,２:23−31（1990）に述べられている条件で行われた
第１図の触媒活性分子を含む切断反応を表す。
実施例１ 第１図の触媒活性分子はApplied Biosystems,Incで製
造されている自動オリゴヌクレオチド合成機を利用して
周知の方法により合成された。
触媒活性分子のリボヌクレアーゼＡによる消化の結果
は第３図Ａに示されている。
上記のようにして、生産された触媒活性分子は、それ
ぞれ610ヌクレオチド（Ｓ−610）と170ヌクレオチドのH
IV−１ gag転写産物の切断に用いられた。要約する
と、緩衝液は標的分子およそ1 pmol,DNAあるいはリボザ
イム3 pmolにつき50mM Tris−HCl,pH7.5,1mM EDTA,10mM
MgCl2であった。反応は37℃において12時間行われた。
基質はHIV−１ gag転写産物を含む610ヌクレオチド
（Ｓ−610）とHIV−１ gag転写産物を含む172ヌクレオ
チド（Ｓ−172）のいずれかである。両方のヌクレオチ
ドともに５′切断産物を示した。
第３図Ｂにおいて５′切断産物は両方の転写産物につ
いて示されている。標的物610の３′切断産物はオート
ラジオグラフィーにおける再現には量的に乏しいので見
えない、しかし３′Ｐの決定法によりその位置が示され
る。ネガティブコントロールとして、DRDRD配列と等し
い塩基配列をもった全DNAオリゴヌクレオチド（Ｄ）を
同じ条件で同じ基質を用いてインキュベートしたが、切
断は起こらなかった。
同じ触媒活性分子をもちいたHIV−１の５′LTRスプラ
イス部位の特異的な切断も起こすことができた。
───────────────────────────────────────────────────── フロントページの続き (72)発明者 カプラン，ブルース・イー アメリカ合衆国カリフォルニア州91711, クレアモント，ノース・インディアン・ ヒル 825 (58)調査した分野(Int.Cl.7，ＤＢ名) ＢＩＯＳＩＳ（ＤＩＡＬＯＧ) ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ) ＷＰＩ（ＤＩＡＬＯＧ)

Claims (7)

    (57)【特許請求の範囲】
  1. 【請求項１】下記の式： で表される触媒活性分子であって、 式中、ＸおよびＺはリボザイムの既知の切断部位と近接
    した位置において、RNA基質と相補対を形成するDNA塩基
    配列であり、AAAG、CAAAGおよびAGUAGUCはRNA塩基配列
    を表し、Ｙは前記各RNA塩基配列が前記切断部位におい
    て前記RNA基質を切断することことができるために必要
    とされる様式で自己の内部で相補対を形成するDNA塩基
    配列である、 前記リボザイム切断部位においてHIV−１のRNA塩基配列
    を切断することができる前記触媒活性分子。
  2. 【請求項２】５′−CCGCTTAATA CTCUGAUGAG TCCGTGAGGA
    CGAAACGCTC TCGCACC−３′の配列を有する、請求項１
    に記載の触媒活性分子。
  3. 【請求項３】５′−TTTTGGCGCU GAUGAGTCCG TGAGGACGAA
    ACTCTCCAGT CG−３′の配列を有する、請求項１に記載
    の触媒活性分子。
  4. 【請求項４】前記RNA基質がHIV−１の塩基配列である、
    請求項１に記載の触媒活性分子。
  5. 【請求項５】前記HIV−１のRNA基質が、５′−GGUGCGAG
    AG CGUCAGUAUU AAGCGG−３′の配列を有する、請求項４
    に記載の触媒活性分子。
  6. 【請求項６】前記HVI−１のRNA基質が、５′−CGACUGGU
    GA GUACGCCAAA A−３′の配列を有する、請求項４に記
    載の触媒活性分子。
  7. 【請求項７】第1DNA部分−触媒活性RNA部分−第３のDNA
    塩基配列−触媒活性RNA部分−第2DNA部分の構造を有す
    るRNA塩基配列を切断することのできる触媒活性分子で
    あって、前記第１および第2DNA部分は切断部位周辺の各
    基質RNA塩基配列と相補対を形成することができ、前記
    第３のDNA塩基配列は前記切断を促進するように自己の
    内部で相補対を形成する、前記触媒活性分子。
JP50884090A 1989-08-31 1990-06-05 キメラｄｎａ―ｒｎａ触媒活性配列 Expired - Fee Related JP3058686B2 (ja)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US40161389A 1989-08-31 1989-08-31
US401,613 1989-08-31

Publications (2)

Publication Number Publication Date
JPH04502256A JPH04502256A (ja) 1992-04-23
JP3058686B2 true JP3058686B2 (ja) 2000-07-04

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Country Link
EP (1) EP0451221B1 (ja)
JP (1) JP3058686B2 (ja)
AU (1) AU637800B2 (ja)
CA (1) CA2039718C (ja)
GB (1) GB2242432B (ja)
WO (1) WO1991003162A1 (ja)

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