Drug discovery driven by structural plasticity of RNA

• Project/Area Number: 24241074
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Chemical biology
• Research Institution: The University of Tokyo
• Principal Investigator: Nakamura Yoshikazu 東京大学, 医科学研究所, 名誉教授 (40114590)
• Project Period (FY): 2012-10-31 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥45,110,000 (Direct Cost: ¥34,700,000、Indirect Cost: ¥10,410,000); Fiscal Year 2015: ¥11,440,000 (Direct Cost: ¥8,800,000、Indirect Cost: ¥2,640,000); Fiscal Year 2014: ¥11,440,000 (Direct Cost: ¥8,800,000、Indirect Cost: ¥2,640,000); Fiscal Year 2013: ¥11,310,000 (Direct Cost: ¥8,700,000、Indirect Cost: ¥2,610,000); Fiscal Year 2012: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000)
• Keywords: アプタマー / SELEX / 核酸医薬 / 創薬標的 / アンタゴニスト / アゴニスト / RNA造形力 / 構造生物学 / RNAアプタマー / 疾患標的タンパク質

Outline of Final Research Achievements

Aptamer is a folded single-stranded nucleic acid that binds given molecules. The concept is based on the ability of short (20-80 mer) sequences to fold, in the presence of a target, into unique three-dimensional structures, which allow the aptamer to bind target molecules with high affinity and specificity. In this study, we developed several RNA and/or DNA aptamers by SELEX method to therapeutic target proteins such as Midkine, Autotaxin and FGF2. The therapeutic potency of these aptamers for cancer, fibrosis and bone diseases, respectively, was confirmed in the in vitro (cell-based) and in vivo (animal-based) studies. In collaboration with O. Nureki’s group of The University of Tokyo, we solved the crystal structure of Autotaxin complexed with the aptamer at the 2.0 angstrom resolution, uncovering the inhibitory mechanism and the structure-function relationship.

Research Products

• [Journal Article] Structural basis for specific inhibition of Autotaxin by a DNA aptamer (2016)
  • Author(s): Kato, K., Ikeda, H., Miyakawa, S., Futakawa, S., Nonaka, Y., Fujiwara, M., Aoki, J., Morita, J., Ishitani, R., Nishimasu, H., Nakamura, Y., Nureki, O.
  • Journal Title: Nat Struct Mol Biol Volume: 印刷中 Pages: 395-401
  • DOI: 10.1038/nsmb.3200
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A functional involvement of ABCE1, eukaryotic ribosome recycling factor, in nonstop mRNA decay in Drosophila melanogaster cells (2014)
  • Author(s): (206)Kashima, I., Takahashi, M., Hashimoto, Y., Sakota, E., Nakamura, Y., Inada, T.
  • Journal Title: Biochimie Volume: 106 Pages: 10-16
  • DOI: 10.1016/j.biochi.2014.08.001
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Solution structure of a DNA mimicking motif of an RNA aptamer against transcription factor AML1 Runt domain (2013)
  • Author(s): Nomura, Y., Tanaka, Y., Fukunaga, J., Fujiwara, K., Chiba, M., Iibuchi, H., Tanaka, T., Nakamura, Y., Kawai, G., Kozu, T., Sakamoto, T.
  • Journal Title: J Biochem Volume: 154 Pages: 513-519
  • DOI: 10.1093/jb/mvt082
  • Peer Reviewed
• [Journal Article] Clearance of yeast eRF-3 prion [PSI+] by amyloid enlargement due to the imbalance between chaperone Ssa1 and cochaperone Sgt2 (2013)
  • Author(s): Arai, C., Kurahashi, H., Pack, C.-G.., Sako, Y., and Nakamura, Y.
  • Journal Title: Translation Volume: 1
  • DOI: 10.4161/trla.26574
  • Peer Reviewed
• [Journal Article] Generation of a mouse model with down-regulated U50 snoRNA (SNORD50) expression and its organ-specific phenotypic modulation (2013)
  • Author(s): Soeno, Y., Fujita, K., Kudo, T., Asagiri, M., Kakuta, S., Taya, Y., Shimazu, Y., Sato, K., Kubo, S., Iwakura, Y., Nakamura, Y., Aoba, T.
  • Journal Title: PLoS ONE Volume: 8
  • Peer Reviewed
• [Journal Article] The Runt domain of AML1 (RUNX1) binds a sequence-conserved RNA motif that mimics a DNA element (2013)
  • Author(s): Fukunaga, J., Nomura, Y., Tanaka, Y., Tanaka, T., Nakamura, Y., Kawai, G., Sakamoto, T., Kozu, T.
  • Journal Title: RNA Volume: 19 Pages: 927-936
  • DOI: 10.1261/rna.037879.112
  • Peer Reviewed
• [Journal Article] The RNA aptamer inhibiting human vesicular endothelial growth factor receptor 1 without affecting the cytokine binding (2013)
  • Author(s): Ohuchi, S., Shibuya, M., Nakamura, Y.
  • Journal Title: Biochemistry Volume: 52 Pages: 2274-2279
  • DOI: 10.1021/bi301669p
  • Peer Reviewed
• [Journal Article] Midkine promotes neuroblastoma through Notch2 signaling (2013)
  • Author(s): Kishida S, Mu P, Miyakawa S, Fujiwara M, Abe T, Sakamoto K, Onishi A, Nakamura Y, Kadomatsu K
  • Journal Title: Cancer research Volume: 73(4) Pages: 1318-1327
  • DOI: 10.1158/0008-5472.can-12-3070
  • Peer Reviewed
• [Journal Article] A bipolar functionality of Q/N-rich proteins: Lsm4 amyloid causes clearance of yeast prions (2013)
  • Author(s): Keita Oishi, Hiroshi Kurahashi, Chan-Gi Pack, Yasushi Sako, Yoshikazu Nakamura
  • Journal Title: MicrobiologyOpen Volume: (印刷中) Pages: 415-430
  • DOI: 10.1002/mbo3.83
  • Peer Reviewed
• [Journal Article] Clearance of yeast prions by misfolded multi-transmembrane proteins (2013)
  • Author(s): Chie Arai, Hiroshi Kurahashi, Masao Ishiwata, Keita Oishi, Yoshikazu Nakamura
  • Journal Title: Biochimie Volume: 95 Pages: 1223-1232
  • DOI: 10.1016/j.biochi.2013.01.009
  • Peer Reviewed
• [Journal Article] Evolution of an inhibitory RNA aptamer against T7 RNA polymerase (2012)
  • Author(s): Ohuchi, S., Mori, Y., Nakamura, Y
  • Journal Title: FEBS Open Bio Volume: 2 Pages: 203-207
  • DOI: 10.1016/j.fob.2012.07.004
  • Peer Reviewed
• [Presentation] Development of an efficient Cell-SELEX to generate RNA aptamers against a cell surface protein of interest (2015)
  • Author(s): Takahashi, M., Hashimoto, Y., Sakota, E., Nakamura, Y.
  • Organizer: The Oligonucleotide Therapeutics Society 11th Annual Meeting
  • Place of Presentation: Leiden (Netherlands)
  • Year and Date: 2015-10-11
  • Int'l Joint Research
• [Presentation] Aptamer Therapeutics Targeting Pain and Fibrosis (2015)
  • Author(s): Yoshikazu Nakamura
  • Organizer: 18th A-IMBN Annual Conference & SIMS Opening Ceremony
  • Place of Presentation: Cheonan Korea
  • Year and Date: 2015-09-21
  • Int'l Joint Research / Invited
• [Presentation] Therapeutic Aptamer Discovery by RiboART System (2015)
  • Author(s): Yoshikazu Nakamura
  • Organizer: 第５３回日本生物物理学会年会
  • Place of Presentation: 石川県金沢市
  • Year and Date: 2015-09-13
  • Invited
• [Presentation] Therapeutic Aptamer Discovery by the RiboART SystemTargeting Lung Fibrosis (2015)
  • Author(s): Yoshikazu Nakamura
  • Organizer: 16th Annual TIDES
  • Place of Presentation: San Diego（USA)
  • Year and Date: 2015-05-03
  • Int'l Joint Research / Invited
• [Presentation] Aptamer Therapeutics Targeting Pain and Lung Fibrosis (2015)
  • Author(s): Nakamura, Y.
  • Organizer: Aptamers 2015
  • Place of Presentation: Oxford, UK
  • Year and Date: 2015-03-31
  • Invited
• [Presentation] Aptamer Therapeutics Targeting Lung Fibrosis (2014)
  • Author(s): Nakamura, Y.
  • Organizer: 17th A-IMBN Annual Conference
  • Place of Presentation: Manila, Philippines
  • Year and Date: 2014-12-01 – 2014-12-02
  • Invited
• [Presentation] 抗IL-17アプタマーはC57BL/6JマウスにおけるIL-23誘導乾癬様皮膚炎を抑制する (2014)
  • Author(s): 長嶺誠和、大瀧菜月、森 重之、佐々木麻子、平本真介、春田和彦、石黒 亮、中村義一
  • Organizer: 第３７回日本分子生物学会年会
  • Place of Presentation: 横浜市
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] AML1 Runt domainとRNAアプタマーの相互作用のNMR解析 (2014)
  • Author(s): 高田健太、天野亨、永田崇、片平正人、野村祐介、田中陽一郎、中村義一、神津知子、坂本泰一
  • Organizer: 第３７回日本分子生物学会年会
  • Place of Presentation: 横浜市
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] RNAアプタマーを用いた新規医用材料の開発 (2014)
  • Author(s): 野村祐介、福井千恵、戸井田瞳、新見伸吾、宮川伸、金玲、中村義一、蓜島由二
  • Organizer: 第36回日本バイオマテリアル学会
  • Place of Presentation: 東京
  • Year and Date: 2014-11-17 – 2014-11-18
• [Presentation] Improvement of the stability of RNA aptamers against Interleukin-17A. (2014)
  • Author(s): Otaki, N., Sasaki, A., Hiramoto, S., Nagamine, M., Mori, S., Kayo, T., Hota, K., Takahashi, M., Haruta, K., Nakamura, Y.
  • Organizer: American College of Rheumatoloty
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-14 – 2014-11-19
• [Presentation] Characterization of RNA aptamer targeting the DNA binding domain of AML1 protein (2014)
  • Author(s): Takada, K., Amano, R., Tanaka, Y., Nagata, T., Katahira, M., Nakamura, Y., Kozu, T., Sakamoto, T.
  • Organizer: 第41回 国際核酸化学シンポジウム
  • Place of Presentation: 北九州市
  • Year and Date: 2014-11-05 – 2014-11-07
• [Presentation] A eRF3-targeted novel regulatory system in gene expression and apoptosis (2014)
  • Author(s): Hashimoto, Y., Hoshino, S.-I., Nakamura, Y.
  • Organizer: Joint Australia and Japan RNA Meeting
  • Place of Presentation: Sydney, Australia
  • Year and Date: 2014-11-02 – 2014-11-05
• [Presentation] Application of atypical RNAi for human diseases (2014)
  • Author(s): Takahashi,M., Nakamura, Y., Hohjoh, H.
  • Organizer: Joint Australia and Japan RNA (jajRNA) meeting
  • Place of Presentation: Sydney, Australia
  • Year and Date: 2014-11-02 – 2014-11-05
• [Presentation] Properties of RNA aptamer binding to AML1 Runt domain (2014)
  • Author(s): Amano, R., Nomura, Y., Nagata, T., Kobayashi, N., Mori, Y., Takada, K., Fukunaga, J., Tanaka, Y., Katahira, M., Nakamura, Y., Kozu, T., Sakamoto, T.
  • Organizer: XXI Round Table on Nucleosides, Nucleotides and Nucleic Acids
  • Place of Presentation: Poznan, Poland
  • Year and Date: 2014-08-24 – 2014-08-28
• [Presentation] ショウジョウバエ細胞においてリボソームリサイクリング因子ABCE1はNonstop mRNA decayに関与する (2014)
  • Author(s): 鹿島勳、迫田絵理、中村義一、稲田利文
  • Organizer: 第１６回に本RNA学会年会
  • Place of Presentation: 名古屋市
  • Year and Date: 2014-07-23 – 2014-07-25
• [Presentation] A sequence-conserved RNA motif binds to the DNA-recognition site of AML1 (2014)
  • Author(s): Kozu, T., Fukunaga, J., Nomura, Y., Tanaka, Y., Amano, R., Tanaka, T., Nakamura, Y., Kawai, G., Sakamoto, T.
  • Organizer: 第７３回日本癌学会学術総会
  • Place of Presentation: 横浜市
  • Year and Date: 2014-06-25 – 2014-06-27
• [Presentation] NMRによるAML1タンンパク質をRNAアプタマーの相互作用の解析 (2014)
  • Author(s): 天野亨、野村祐介、永田崇、小林直宏、高田健太、福永淳一、田中陽一郎、片平正人、中村義一、神津知子、坂本泰一
  • Organizer: 日本分光発光学会年次講演会
  • Place of Presentation: 和光市
  • Year and Date: 2014-05-26 – 2014-05-28
• [Presentation] The RNA aptamer against midkine suppresses neuroblastoma xenograft growth by attenuating midkine-Notch2 pathway (2014)
  • Author(s): Kishida, S., Mu, P., Miyakawa, S., Fujiwara, M., Abe, T., Sakamoto, K., Nakamura, Y., Kadomatsu, K.
  • Organizer: Advances in Neuroblastoma Research
  • Place of Presentation: Cologne, Germany
  • Year and Date: 2014-05-13 – 2014-05-16
• [Presentation] Therapeutic Aptamer Discovery by the RiboART System (2014)
  • Author(s): Y. Nakamura
  • Organizer: 6th Annual AsiaTIDES
  • Place of Presentation: 東京
  • Invited
• [Presentation] 転写因子AML1に対して複数の結合部位を持つ高親和性RNAアプタマーの解析 (2013)
  • Author(s): 天野亨、野村祐介、永田崇、小林直宏、森揺子、福永淳一、田中陽一郎、片平正人、中村義一、神津知子、坂本泰一
  • Organizer: 第36回分子生物学会年会
  • Place of Presentation: 神戸
• [Presentation] Mluti-site binding of high affinity aptamer against AML1 Runt domain (2013)
  • Author(s): Ryo Amano, Yusuke Nomura, Takashi Nagata,Naohiro Kobayashi Yoko Mori,Jun-ichi Fukunaga, Yoichiro Tanaka, Masato Katahira, Yoshikazu Nakamura, Tomoko Kozu and Taiichi Sakamoto
  • Organizer: 第40回国際核酸化学シンポジウム
  • Place of Presentation: 神奈川
• [Presentation] Novel Therapeutics for Pain Control with RNA Aptamer against Nerve Growth Factor (2013)
  • Author(s): Yoshikazu Nakamura
  • Organizer: Aptamers in Medicine and Perspectives
  • Place of Presentation: Naples (Italy)
• [Presentation] アプタマー創薬 (2013)
  • Author(s): 中村義一
  • Organizer: 第１５回日本RNA学会年会
  • Place of Presentation: 松山
  • Invited
• [Presentation] 転写因子AML1を標的としたRNAアプタマーによるDNAの擬態 (2013)
  • Author(s): 天野亨、野村祐介、永田崇、森揺子、福永淳一、田中陽一郎、片平正人、中村義一、神津知子、坂本泰一
  • Organizer: 日本ケミカルバイオロジー学会第８回年会
  • Place of Presentation: 東京
• [Presentation] Novel Therapeutics for Pain Control with RNA Aptamer against Nerve Growth Factor (2013)
  • Author(s): Nakamura, Y.
  • Organizer: 1st Gene and Immunotherapy Conference
  • Place of Presentation: Ho Chi Minh City, Vietnam
  • Invited
• [Presentation] 転写因子AML1タンパク質とRNAアプタマーの相互作用解析
  • Author(s): 天野亨、野村祐介、永田崇、森揺子、福永淳一、田中陽一郎、片平正人、中村義一、神津知子、坂本泰一
  • Organizer: 平成２５年度日本生化学会関東支部例会
  • Place of Presentation: 山梨
• [Presentation] RNAの造形力を利用したアプタマー創薬
  • Author(s): 中村義一
  • Organizer: 第４回新たな創薬パラダイムの創出
  • Place of Presentation: 東京
  • Invited
• [Book] アプタマーの創製と医薬開発、「核酸医薬の創製と応用展開」（和田猛監修） (2016)
  • Author(s): 藤原将寿、中村義一
  • Publisher: シーエムシー出版
• [Book] アプタマーを標的とした研究の進展と安全性評価 (2016)
  • Author(s): 野中洋介、藤原将寿、中村義一
  • Publisher: 技術情報協会書籍出版
• [Remarks] 東京大学医科学研究所 RNA医科学社会連携研究部門
  • URL: http://www.ims.u-tokyo.ac.jp/rnaikagaku/top.html
• [Remarks] 東京大学医科学研究所「RNA医科学」社会連携研究部門
  • URL: http://www.ims.u-tokyo.ac.jp/rnaikagaku/top.html
• [Remarks] 東京大学医科学研究所
  • URL: http://www.ims.u-tokyo.ac.jp/imsut/jp/
• [Patent(Industrial Property Rights)] IL-17に対するアプタマー及びその使用 (2014)
  • Inventor(s): 石黒亮、中村義一、春田和彦、君島智代
  • Industrial Property Rights Holder: 全薬工業株式会社、東京大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-03-20
  • Overseas
• [Patent(Industrial Property Rights)] IL-17に対するアプタマー及びその使用 (2013)
  • Inventor(s): 中村義一、石黒亮、春田和彦、君島智代
  • Industrial Property Rights Holder: 全薬工業株式会社、東京大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-060817
  • Filing Date: 2013-03-22
• [Patent(Industrial Property Rights)] ミッドカインに対するアプタマー及びその用途 (2012)
  • Inventor(s): 宮川伸、藤原将寿、中村義一、門松健治、牟萍
  • Industrial Property Rights Holder: 株式会社リボミック、名古屋大
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2012-255588
  • Filing Date: 2012-11-21