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2013 Fiscal Year Final Research Report

Medicinal Application of Functional Machinery for non-coding RNAs

Planned Research

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Project AreaFunctional machinery for non-coding RNAs
Project/Area Number 21115008
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionTokyo University of Science (2013)
The University of Tokyo (2009-2012)

Principal Investigator

WADA Takeshi  東京理科大学, 薬学部, 教授 (90240548)

Co-Investigator(Kenkyū-buntansha) TAKESHITA Fumitaka  独立行政法人国立がん研究センター研究所, 分子細胞治療研究分野, 主任研究員 (40466199)
Project Period (FY) 2009-07-23 – 2014-03-31
Keywords非コードRNA / 核酸医薬 / ホスホロチオエートRNA / 立体制御 / siRNA / がん
Research Abstract

A practical method for the synthesis of stereoregulated phaosphorothioate RNA (PSRNA) was established. By using novel nucleoside oxazaphospholidine monomers, various P-stereoregulated PSRNAs including PS-siRNAs were successfully synthesized. Using the resultant PS-RNAs, we demonstrated that the PS-RNA with an all-Rp-phosphorothioate backbone formed a more stable duplex with the complementary RNA than the unmodified counterpart, whereas duplexes consisting of an all-Sp-PS-RNA or a stereo-random counterpart were significantly destabilized. The stability of PS-siRNA was assessed by treatment with RNA degradation enzymes. The siRNA harboring a single PS bond located from center to 3' side of its sequence and the Sp isomer of PS-siRNA showed higher stabilities compared with the Rp isomer. Furthermore, five consecutive PS bonds on the end of 3'-terminal side of siRNAs more contributed the stabilization of themselves and induction of RNAi activity on a mouse model of human breast cancer.

  • Research Products

    (69 results)

All 2014 2013 2012 2011 2010 2009 Other

All Journal Article (24 results) (of which Peer Reviewed: 22 results) Presentation (26 results) (of which Invited: 14 results) Book (2 results) Remarks (1 results) Patent(Industrial Property Rights) (16 results) (of which Overseas: 9 results)

  • [Journal Article] Solid-phase synthesis of p-boronated oligonucleotides by the H-boranophosphonate method2014

    • Author(s)
      Uehara S, Hiura S, Higashida R, Oka N, Wada T
    • Journal Title

      J. Org. Chem.

      Volume: 79(8) Pages: 3465-72

    • Peer Reviewed
  • [Journal Article] Synthesis and properties of double-stranded RNA-bindable oligodiaminogalactose derivatives conju-gated with vitamin E2014

    • Author(s)
      Iwata R, Nishina K, Yokota, T, Wada T
    • Journal Title

      Bioorg. Med. Chem.

      Volume: 22(4) Pages: 1394-1403

    • Peer Reviewed
  • [Journal Article] Stereoselective synthesis of P-modified α-glycosyl phosphates by the oxazaphospholidine approach2013

    • Author(s)
      Noro M, Fujita S, Wada T
    • Journal Title

      Org. Lett.

      Volume: 15(23) Pages: 5948-51

    • Peer Reviewed
  • [Journal Article] Stereocontrolled synthesis of dinucleoside phosphorothioates using a fluorous tag2013

    • Author(s)
      Oka N, Murakami R, Kondo T, Wada T
    • Journal Title

      J. Fluor. Chem.

      Volume: 150 Pages: 85-91

    • Peer Reviewed
  • [Journal Article] Synthesis and properties of cationic oligopeptides with different side chain lengths that bind to RNA duplexes2013

    • Author(s)
      Maeda Y, Iwata R, Wada T
    • Journal Title

      Bioorg. Med. Chem.

      Volume: 21(7) Pages: 1717-23

    • Peer Reviewed
  • [Journal Article] A novel platform to enable inhaled naked RNAi medicine for lung cancer2013

    • Author(s)
      Fujita Y, Takeshita F,他 4人
    • Journal Title

      Sci. Rep.

      Volume: 3 Pages: 3325

    • DOI

      10.1038/srep03325

    • Peer Reviewed
  • [Journal Article] RNAi therapeutics and applications of microRNAs in cancer treatment2013

    • Author(s)
      Uchino K, Ochiya T, Takeshita F
    • Journal Title

      Jpn. J. Clin. Oncol.

      Volume: 43 Pages: 596-607

    • DOI

      10.1093/jjco/hyt052

    • Peer Reviewed
  • [Journal Article] Therapeutic effects of microRNA-582-5p and -3p on the inhibition of bladder cancer progression2013

    • Author(s)
      Uchino K, Takeshita F,他 12人
    • Journal Title

      Mol Ther.

      Volume: 21 Pages: 610-619

    • DOI

      10.1038/mt.2012.269

    • Peer Reviewed
  • [Journal Article] Intraperitoneal delivery of a small interfering RNA targeting NEDD1 prolongs the survival of scirrhous gastric cancer model mice2013

    • Author(s)
      Fujita T, Yanagihara K, Takeshita F,他 11人
    • Journal Title

      Cancer Sci.

      Volume: 104 Pages: 214-222

    • DOI

      10.1111/cas.12054

    • Peer Reviewed
  • [Journal Article] RNAi Therapeutic Platforms for Lung Diseases2013

    • Author(s)
      Fujita Y, Takeshita F, Kuwano K, Ochiya T
    • Journal Title

      Pharmaceuticals

      Volume: 6 Pages: 223-225

    • DOI

      10.3390/ph6020223

    • Peer Reviewed
  • [Journal Article] Improved method for the solid-phase synthesis of oligoribonucleotide 5´-triphosphates2012

    • Author(s)
      Nagata S, Takagaki K, Wad, T
    • Journal Title

      Chem. Pharm. Bull.

      Volume: 60(9) Pages: 1212-1215

    • Peer Reviewed
  • [Journal Article] Synthesis of nucleoside 5'-boranophosphorothioate derivatives using an H-boranophosphonate monoester as a precursor2012

    • Author(s)
      Oka N, Takayama Y, Ando K, Wada T
    • Journal Title

      Bioorg. Med. Chem. Lett.

      Volume: 22(14) Pages: 4571-4.

    • Peer Reviewed
  • [Journal Article] Stereo-controlled synthesis of oligodeoxyribonucleoside boranophosphates by an oxazaphospholidine approach using acid-labile N-protecting groups2012

    • Author(s)
      Iwamoto N, Oka N, Wada T
    • Journal Title

      Tetrahedron Lett.

      Volume: 53(33) Pages: 4361-4364

    • Peer Reviewed
  • [Journal Article] Stereocontrolled solid-phase synthesis of phosphorothioate oligoribonucleotides using 2'-O-(2-cyanoethoxymethyl)-nucleoside 3'-O-oxazaphospholidine monomers2012

    • Author(s)
      Nukaga Y, Yamada K, Ogata T, Oka N, Wada T
    • Journal Title

      J. Org. Chem.

      Volume: 77(18) Pages: 7913-22

    • Peer Reviewed
  • [Journal Article] In vivo imaging of oligonucleotide delivery2012

    • Author(s)
      Takeshita F, Takahashi RU, Onodera J, Ochiya T
    • Journal Title

      Methods Mol. Biol.

      Volume: 872 Pages: 243-253

    • DOI

      10.1007/978-1-61779-797-2_17

    • Peer Reviewed
  • [Journal Article] Stereocontrolled synthesis of oligonucleotide analogs containing chiral internucleotidic phosphorus atoms2011

    • Author(s)
      Oka N, Wada T
    • Journal Title

      Chem. Soc. Rev.

      Volume: 40(12) Pages: 5829-43

    • Peer Reviewed
  • [Journal Article] Synthesis and properties of novel 2'-O-alkoxymethylmodified nucleic acids2011

    • Author(s)
      Arai K, Uchiyama N, Wada T
    • Journal Title

      Bioorg. Med. Chem. Lett.

      Volume: 21(21) Pages: 6285-7

    • Peer Reviewed
  • [Journal Article] MicroRNA-143 Regulates Human Osteosarcoma Metastasis by Regulating Matrix Metalloprotease-13 Expression2011

    • Author(s)
      Osaki M, Takeshita F,他 11人
    • Journal Title

      Mol Ther.

      Volume: 19 Pages: 1123-1130

    • DOI

      10.1038/mt.2011.53

    • Peer Reviewed
  • [Journal Article] miR-22 represses cancer progression by inducing cellular senescence2011

    • Author(s)
      Xu D, Takeshita F,他 10人
    • Journal Title

      J. Cell Biol.

      Volume: 193 Pages: 409-424

    • DOI

      10.1083/jcb.201010100

    • Peer Reviewed
  • [Journal Article] Solid-phase synthesis of oligodeoxyribonucleotides without base protection utilizing O-selective reaction of oxazaphospholidine derivatives2010

    • Author(s)
      Oka N, Maizuru Y, Shimizu M, Wada T
    • Journal Title

      Nucleos Nucleot Nucl Acids.

      Volume: 29 Pages: 144-145

    • Peer Reviewed
  • [Journal Article] Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell cycle genes2010

    • Author(s)
      Takeshita F,他 11人
    • Journal Title

      Mol. Ther.

      Volume: 18 Pages: 181-187

    • DOI

      10.1038/mt.2009.207

    • Peer Reviewed
  • [Journal Article] Stereo-controlled synthesis of oligodeoxyribonucleoside boranophosphates via stereodefined H-phosphonate intermediates2009

    • Author(s)
      Iwamoto N, Oka N, Wada T
    • Journal Title

      Nucleic Acids Symp Ser.

      Volume: (53) Pages: 9-10

  • [Journal Article] Chemical synthesis of nucleoside H-boranophosphonates and their application as precursors of P-modified nucleotide analogues2009

    • Author(s)
      Oka N, Higashida R, Takayama Y, Ando K, Wada T
    • Journal Title

      Nucleic Acids Symp Ser.

      Volume: (53) Pages: 111-2

  • [Journal Article] Local and systemic delivery of siRNAs for oligonucleotides therapy2009

    • Author(s)
      Takeshita F, Hokaiwado N, Honma K, Banas A and Ochiya T
    • Journal Title

      Methods in Mol. Biol.

      Volume: 487 Pages: 83-92

    • DOI

      10.1007/978-1-60327-547-7_4

    • Peer Reviewed
  • [Presentation] 核酸医薬への合成化学的アプローチ2014

    • Author(s)
      和田猛
    • Organizer
      第25回歯工学連携講演会
    • Place of Presentation
      九州工業大学、北九州
    • Year and Date
      20140100
    • Invited
  • [Presentation] miRNAとエクソソームのがん診断への応用2013

    • Author(s)
      竹下文隆
    • Organizer
      第34回日本臨床薬理学会学術総会
    • Place of Presentation
      東京
    • Year and Date
      20131200
    • Invited
  • [Presentation] 乳がん再発に関与する Long Non-Coding RNAの探索2013

    • Author(s)
      竹下文隆、他 4人
    • Organizer
      第72回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      20131000
  • [Presentation] 乳がんの悪性化に関与する長鎖非コード RNAの探索2013

    • Author(s)
      竹下文隆、他 4人
    • Organizer
      第4回日本RNAi研究会
    • Place of Presentation
      広島
    • Year and Date
      20130800
  • [Presentation] リン原子修飾核酸医薬の立体制御2013

    • Author(s)
      和田猛
    • Organizer
      Symposium on Innovative Research at KUT Part 1
    • Place of Presentation
      高知工科大学、高知
    • Year and Date
      20130700
    • Invited
  • [Presentation] New synthetic strategies for RNA drugs2013

    • Author(s)
      和田猛
    • Organizer
      第15回RNAミーティング
    • Place of Presentation
      愛媛県・県民文化会館、愛媛
    • Year and Date
      20130700
    • Invited
  • [Presentation] 有機合成で創り出す核酸医薬への新しいアプローチ2013

    • Author(s)
      和田猛
    • Organizer
      第23回万有福岡シンポジウム
    • Place of Presentation
      九州大学、福岡
    • Year and Date
      20130600
    • Invited
  • [Presentation] リン原子修飾核酸医薬の立体制御、次世代医薬「核酸医薬」創出に向けた Strategy2013

    • Author(s)
      和田猛
    • Organizer
      次世代医薬「核酸医薬」創出に向けた Strategy
    • Place of Presentation
      コクヨホール、東京
    • Year and Date
      20130400
    • Invited
  • [Presentation] Therapeutics application of microRNA-582-5p and -3p in the treatment of invasive bladder cancer2013

    • Author(s)
      K. Uchino, F. Takeshita,他 3人
    • Organizer
      Keystone Symposia: Non-Coding RNAs in Development and Cancer
    • Place of Presentation
      バンクーバー、カナダ
    • Year and Date
      20130100
  • [Presentation] 医薬品を志向した機能性キラル核酸の創成2012

    • Author(s)
      和田猛
    • Organizer
      第40回バイオインターフェース
    • Place of Presentation
      全理連ビル、東京
    • Year and Date
      20121200
    • Invited
  • [Presentation] microRNA-582-5pおよび3p鎖の両鎖機能性による膀胱がん細胞の増殖、浸潤抑制効果2012

    • Author(s)
      内野慧太、竹下文隆、他 12人
    • Organizer
      第35回日本分子生物学会年会
    • Place of Presentation
      福岡市
    • Year and Date
      20121200
  • [Presentation] Stereocontrolled synthesis and properties of P-chiral oligonucleotides2012

    • Author(s)
      和田猛
    • Organizer
      8th Annual Meeting of the Oligonucleotide Therapeutics Society 2012
    • Place of Presentation
      ハーバード大学、アメリカ
    • Year and Date
      20121000
    • Invited
  • [Presentation] microRNA-582-5p/3pによる膀胱がんの増殖および転移の抑制2012

    • Author(s)
      内野慧太、竹下文隆、他 5人
    • Organizer
      第71回日本癌学会学術総会
    • Place of Presentation
      札幌市
    • Year and Date
      20120900
  • [Presentation] 浸潤性膀胱がんに対する新規核酸医薬の開発2012

    • Author(s)
      内野慧太、竹下文隆、他 5人
    • Organizer
      第4回日本RNAi研究会
    • Place of Presentation
      広島市
    • Year and Date
      20120800
  • [Presentation] ゲノムコピー数変化を指標としたヒト乳がん細胞株の薬剤耐性獲得に関与する microRNAの探索2012

    • Author(s)
      竹下文隆、他 7人
    • Organizer
      第4回日本RNAi研究会
    • Place of Presentation
      広島市
    • Year and Date
      20120800
  • [Presentation] 薬として働く核酸分子を化学の力で組み立てる2012

    • Author(s)
      和田猛
    • Organizer
      第7回理研「バイオものづくり」シンポジウム
    • Place of Presentation
      理化学研究所和光キャンパス、和光市
    • Year and Date
      20120300
    • Invited
  • [Presentation] P-Chiral Nucleic Acids as New Therapeutic Agents2011

    • Author(s)
      和田猛
    • Organizer
      第34回日本分子生物学会年会
    • Place of Presentation
      パシフィコ横浜、横浜
    • Year and Date
      20111200
    • Invited
  • [Presentation] 膀胱がんの悪性化に関与するmicroRNAの同定と機能解析2011

    • Author(s)
      内野慧太、竹下文隆、他 3人
    • Organizer
      第70回日本癌学会学術総会
    • Place of Presentation
      名古屋市
    • Year and Date
      20111000
  • [Presentation] 核酸医薬の新機軸2011

    • Author(s)
      和田猛
    • Organizer
      第38回BMBコンファレンス
    • Place of Presentation
      箱根高原ホテル、神奈川
    • Year and Date
      20110700
    • Invited
  • [Presentation] リン原子修飾核酸医薬の化学的創製2011

    • Author(s)
      和田猛
    • Organizer
      第8回分子複合医薬研究会
    • Place of Presentation
      産業技術総合研究所関西センター、大阪
    • Year and Date
      20110700
    • Invited
  • [Presentation] リン原子修飾核酸医薬の化学的創製2011

    • Author(s)
      和田猛
    • Organizer
      第27回日本DDS学会
    • Place of Presentation
      東京大学、東京
    • Year and Date
      20110600
    • Invited
  • [Presentation] MicroRNA Therapy for Inhibition of Lung Metastasis of Osteosarcoma2011

    • Author(s)
      Takeshita, F.,他 6人
    • Organizer
      Keystone Symposia-J5: MicroRNAs and Non-Coding, RNAs and Cancerバンフ
    • Place of Presentation
      カナダ
    • Year and Date
      20110200
  • [Presentation] New aspects for the chemical synthesis of backbone-modified nucleic acids as therapeutic agents2010

    • Author(s)
      和田猛
    • Organizer
      2010 The International Chemical Congress of Pacific Basin Societies
    • Place of Presentation
      ハワイコンベンションセンター、アメリカ
    • Year and Date
      20101200
    • Invited
  • [Presentation] Identification and functional analysis of deregulated microRNA located in aberrant genomic region in bradder cancer patients and cell lines2010

    • Author(s)
      Uchino, K., Takeshita, F.,他 4人
    • Organizer
      第33回日本分子生物学会年会
    • Place of Presentation
      神戸市
    • Year and Date
      20101200
  • [Presentation] microRNAを用いた膀胱がんに対する新規核酸医薬の開発2010

    • Author(s)
      内野慧太、竹下文隆、他 3人
    • Organizer
      第3回日本RNAi研究会
    • Place of Presentation
      広島市
    • Year and Date
      20100800
  • [Presentation] microRNA投与による転移性前立腺がんに対する新規治療法の開発2010

    • Author(s)
      竹下文隆、落谷孝広
    • Organizer
      第2回日本RNAi研究会
    • Place of Presentation
      広島市
    • Year and Date
      20100800
  • [Book] フルオラスケミストリーの基礎と応用2010

    • Author(s)
      和田猛(共著)
    • Publisher
      CMC出版
  • [Book] 10. RNA工学の基礎と応用2010

    • Author(s)
      和田猛(共著)
    • Publisher
      CMC出版
  • [Remarks]

    • URL

      http://mcm.ncc.go.jp

  • [Patent(Industrial Property Rights)] 二重鎖核酸結合剤、当該結合剤二重鎖核酸複合体、当該複合体を含有する医薬品組成物、及び、当該複合体の製造方法2014

    • Inventor(s)
      和田猛, 他
    • Industrial Property Rights Holder
      和田猛, 他
    • Industrial Property Number
      PCT/JP2014/5785
    • Filing Date
      2014-03-20
    • Overseas
  • [Patent(Industrial Property Rights)] ボラノホスフェート化合物、及び核酸オリゴマー2013

    • Inventor(s)
      和田猛, 他
    • Industrial Property Rights Holder
      和田猛, 他
    • Industrial Property Number
      特願 2013-234384
    • Filing Date
      2013-11-12
  • [Patent(Industrial Property Rights)] β-Hairpin Peptides Which Bind to Nucleic Acid Duplexes2013

    • Inventor(s)
      和田猛, 他
    • Industrial Property Rights Holder
      和田猛, 他
    • Industrial Property Number
      US 61/888,200
    • Filing Date
      2013-10-08
    • Overseas
  • [Patent(Industrial Property Rights)] 二重鎖核酸結合剤、当該結合剤二重鎖核酸複合体、当該複合体を含有する医薬品組成物、及び、当該複合体の製造方法2013

    • Inventor(s)
      和田猛, 他
    • Industrial Property Rights Holder
      和田猛, 他
    • Industrial Property Number
      特願 2013-057521
    • Filing Date
      2013-03-21
  • [Patent(Industrial Property Rights)] 中性条件下除去可能な2'-水酸基保護基を用いるRNAの製造法2012

    • Inventor(s)
      和田猛, 他
    • Industrial Property Rights Holder
      和田猛, 他
    • Industrial Property Number
      US61/600,095
    • Filing Date
      2012-02-19
    • Overseas
  • [Patent(Industrial Property Rights)] 2'-O-修飾 RNA2011

    • Inventor(s)
      和田猛, 他
    • Industrial Property Rights Holder
      和田猛, 他
    • Industrial Property Number
      PCT/JP2011/077313
    • Filing Date
      2011-11-28
    • Overseas
  • [Patent(Industrial Property Rights)] リボヌクレオシドホスホロチオエートの製造方法2011

    • Inventor(s)
      和田猛, 他
    • Industrial Property Rights Holder
      和田猛, 他
    • Industrial Property Number
      PCT/JP2011/055018
    • Filing Date
      2011-03-09
    • Overseas
  • [Patent(Industrial Property Rights)] 糖1-リン酸誘導体の立体選択的製造方法2011

    • Inventor(s)
      和田猛, 他
    • Industrial Property Rights Holder
      和田猛, 他
    • Industrial Property Number
      特願 2011-048824
    • Filing Date
      2011-03-09
  • [Patent(Industrial Property Rights)] 2'-O-修飾 RNA2010

    • Inventor(s)
      和田猛, 他
    • Industrial Property Rights Holder
      和田猛, 他
    • Industrial Property Number
      US61/418,384
    • Filing Date
      2010-11-30
    • Overseas
  • [Patent(Industrial Property Rights)] リボヌクレオシドホスホロチオエートの製造方法2010

    • Inventor(s)
      和田猛, 他
    • Industrial Property Rights Holder
      和田猛, 他
    • Industrial Property Number
      特願 2010-048824
    • Filing Date
      2010-03-05
  • [Patent(Industrial Property Rights)] リボヌクレシドH-ボラノホスホネート2010

    • Inventor(s)
      和田猛, 他
    • Industrial Property Rights Holder
      和田猛, 他
    • Industrial Property Number
      特願 2010-048823
    • Filing Date
      2010-03-05
  • [Patent(Industrial Property Rights)] リン酸化試薬2010

    • Inventor(s)
      和田猛, 他
    • Industrial Property Rights Holder
      和田猛, 他
    • Industrial Property Number
      特願 2010-010260
    • Filing Date
      2010-03-09
  • [Patent(Industrial Property Rights)] オリゴアミノ糖化合物2010

    • Inventor(s)
      和田猛, 他
    • Industrial Property Rights Holder
      和田猛, 他
    • Industrial Property Number
      PCT/JP2010/054282
    • Filing Date
      2010-03-09
    • Overseas
  • [Patent(Industrial Property Rights)] 二重鎖RNA結合性オリゴアミノ糖2010

    • Inventor(s)
      和田猛, 他
    • Industrial Property Rights Holder
      和田猛, 他
    • Industrial Property Number
      US/12/659425
    • Filing Date
      2010-03-09
    • Overseas
  • [Patent(Industrial Property Rights)] 糖1-リン酸化合物の製造方法2010

    • Inventor(s)
      和田猛, 他
    • Industrial Property Rights Holder
      和田猛, 他
    • Industrial Property Number
      特願 2010-050194
    • Filing Date
      2010-03-08
  • [Patent(Industrial Property Rights)] COMPOSITIONS AND METHODS RELATED TO MIR-16 AND THERAPY OF PROSTATE CANCER2009

    • Inventor(s)
      D. Brown, T. Ochiya, F. Takeshita
    • Industrial Property Rights Holder
      D. Brown, T. Ochiya, F. Takeshita
    • Industrial Property Number
      PCT/US2009/038399
    • Filing Date
      2009-03-26
    • Overseas

URL: 

Published: 2015-06-25   Modified: 2015-07-02  

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