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Creation of repeat binding molecules that specifically modify repeat sequences chemically

Research Project

Project/Area Number 19H00924
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Review Section Medium-sized Section 37:Biomolecular chemistry and related fields
Research InstitutionOsaka University

Principal Investigator

Nakatani Kazuhiko  大阪大学, 産業科学研究所, 教授 (70237303)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥45,630,000 (Direct Cost: ¥35,100,000、Indirect Cost: ¥10,530,000)
Fiscal Year 2021: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000)
Fiscal Year 2020: ¥15,860,000 (Direct Cost: ¥12,200,000、Indirect Cost: ¥3,660,000)
Fiscal Year 2019: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Keywordsリピート病 / 結合分子 / 化学修飾 / 修復酵素 / DNA / リピート / 異常伸長 / シトシン / リピート配列 / 低分子 / リピート短縮 / デアミナーゼ / 短縮
Outline of Research at the Start

本申請研究「リピート結合分子によるリピート短縮誘導活性化」は、トリヌクレオチドリピート病の原因となる「異常伸長した(CXG)nリピートの短縮誘導を加速する新規リピート結合分子」の開発を目的とする。具体的には、異常伸長リピートに特異的に結合し、リピート配列が形成するヘアピン内のシトシンをウラシルへ化学的に変換する反応を加速する分子の創成を目指す。リピート長の短縮を誘導するリピート結合分子は、リピート配列の遺伝的不安定性のメカニズムを探る分子ツールを提供すると同時に、リピート病の発症や進行を抑える治療法の端緒となることが期待される。

Outline of Final Research Achievements

The repeat shortening effect we developed was thought to be due to the fixation of the slip-out structure formed during transcription, which affects recognition by DNA repair factors and results in shorter repeat lengths. Inspired by this idea, we aimed to develop "a novel repeat-binding molecule that accelerates the induction of shortening of abnormally elongated (CXG)n repeats." Using the CGG repeat-binding molecule as a model, we synthesized NCD-epoxy with an electrophilically active epoxy group, but it was chemically unstable. On the other hand, by using APOBEC family proteins, which are cytosine deaminases, we found that cytosine on the repeat sequence can be used as a substrate.

Academic Significance and Societal Importance of the Research Achievements

脆弱X症候群、ハンチントン病、筋強直性ジストロフィーなどのリピート病は、ヒトゲノム中のリピート配列の異常伸長や異常挿入を原因とする遺伝性の神経変性疾患であり、リピート伸長抑制による発症抑制等の根治療法や症状緩和等のQOL改善法が待ち望まれている。本研究はこれら不治の疾患に対する治療介入の手法として、リピート結合分子の効果を基礎化学的な側面から検討したものである。今回合成した分子には化学的な安定性と高い化学反応性という相反する性質が求められたため、望む化合物を得ることはできなかったが、より精緻な分子設計により克服することができれば、難治性疾患に悩む多くの方の一助となると考えられる。

Report

(5 results)
  • 2022 Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • 2019 Comments on the Screening Results   Annual Research Report
  • Research Products

    (22 results)

All 2023 2022 2021 2020 Other

All Int'l Joint Research (1 results) Journal Article (21 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 21 results,  Open Access: 13 results)

  • [Int'l Joint Research] Sick Kids Institute(カナダ)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] A small molecule binding to TGGAA pentanucleotide repeats that cause spinocerebellar ataxia type 312023

    • Author(s)
      Shibata Tomonori、Nakatani Kazuhiko
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 79 Pages: 129082-129082

    • DOI

      10.1016/j.bmcl.2022.129082

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Possibilities and challenges of small molecule organic compounds for the treatment of repeat diseases2022

    • Author(s)
      NAKATANI Kazuhiko
    • Journal Title

      Proceedings of the Japan Academy, Series B

      Volume: 98 Issue: 1 Pages: 30-48

    • DOI

      10.2183/pjab.98.003

    • NAID

      130008140767

    • ISSN
      0386-2208, 1349-2896
    • Year and Date
      2022-01-11
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] HT-SELEX-based identification of binding pre-miRNA hairpin-motif for small molecules2022

    • Author(s)
      Mukherjee Sanjukta、Murata Asako、Ishida Ryoga、Sugai Ayako、Dohno Chikara、Hamada Michiaki、Krishna Sudhir、Nakatani Kazuhiko
    • Journal Title

      Molecular Therapy - Nucleic Acids

      Volume: 27 Pages: 165-174

    • DOI

      10.1016/j.omtn.2021.11.021

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mismatch binding ligand upregulated back-splicing reaction producing circular RNA in a cellular model2022

    • Author(s)
      Ni Lu、Yamada Takeshi、Murata Asako、Nakatani Kazuhiko
    • Journal Title

      Chemical Communications

      Volume: 58 Issue: 22 Pages: 3629-3632

    • DOI

      10.1039/d1cc06936e

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] CAG repeat-binding small molecule improves motor coordination impairment in a mouse model of Dentatorubral?pallidoluysian atrophy2022

    • Author(s)
      Hasuike Yuhei、Tanaka Hana、Gall-Duncan Terence、Mehkary Mustafa、Nakatani Kazuhiko、Pearson Christopher E.、Tsuji Shoji、Mochizuki Hideki、Nakamori Masayuki
    • Journal Title

      Neurobiology of Disease

      Volume: 163 Pages: 105604-105604

    • DOI

      10.1016/j.nbd.2021.105604

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Premature translation termination mediated non-ER stress induced ATF6 activation by a ligand-dependent ribosomal frameshifting circuit2022

    • Author(s)
      Hsu Hsiu-Ting、Murata Asako、Dohno Chikara、Nakatani Kazuhiko、Chang KungYao
    • Journal Title

      Nucleic Acids Research

      Volume: 50 Issue: 9 Pages: 5369-5383

    • DOI

      10.1093/nar/gkac257

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] NMR determination of the 2:1 binding complex of naphthyridine carbamate dimer (NCD) and CGG/CGG triad in double-stranded DNA2022

    • Author(s)
      Yamada Takeshi、Furuita Kyoko、Sakurabayashi Shuhei、Nomura Makoto、Kojima Chojiro、Nakatani Kazuhiko
    • Journal Title

      Nucleic Acids Research

      Volume: 50 Issue: 17 Pages: 9621-9631

    • DOI

      10.1093/nar/gkac740

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Method for Identifying Sequence Motifs in Pre-miRNAs for Small-Molecule Binding2022

    • Author(s)
      Takashima Yusuke、Murata Asako、Iida Kei、Sugai Ayako、Hagiwara Masatoshi、Nakatani Kazuhiko
    • Journal Title

      ACS Chemical Biology

      Volume: 17 Issue: 10 Pages: 2817-2827

    • DOI

      10.1021/acschembio.2c00452

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibitory Effects of Mismatch Binding Molecules on the Repair Reaction of Uracil-Containing DNA2022

    • Author(s)
      Ulhusna Anisa、Murata Asako、Nakatani Kazuhiko
    • Journal Title

      Biochemistry

      Volume: 61 Issue: 22 Pages: 2522-2530

    • DOI

      10.1021/acs.biochem.2c00344

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 2-Amino-1,8-naphthyridine Dimer (ANP77), a High-Affinity Binder to the Internal Loops of C/CC and T/CC Sites in Double-Stranded DNA2021

    • Author(s)
      Das Bimolendu、Nagano Konami、Kawai Gota、Murata Asako、Nakatani Kazuhiko
    • Journal Title

      The Journal of Organic Chemistry

      Volume: 87 Issue: 1 Pages: 340-350

    • DOI

      10.1021/acs.joc.1c02383

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Small Molecule-Induced Dimerization of Hairpin RNA Interfered with the Dicer Cleavage Reaction2021

    • Author(s)
      Murata Asako、Mori Yuki、Di Yue、Sugai Ayako、Das Bimolendu、Takashima Yusuke、Nakatani Kazuhiko
    • Journal Title

      Biochemistry

      Volume: 60 Issue: 4 Pages: 245-249

    • DOI

      10.1021/acs.biochem.0c00920

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Speeding drug discovery targeting RNAs: An iterative “RNA selection-compounds screening cycle“ for exploring RNA-small molecule pairs2021

    • Author(s)
      Furuzono Tomoko、Murata Asako、Okuda Satoshi、Mizutani Kenji、Adachi Tsuyoshi、Nakatani Kazuhiko
    • Journal Title

      Bioorganic & Medicinal Chemistry

      Volume: 36 Pages: 116070-116070

    • DOI

      10.1016/j.bmc.2021.116070

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Small molecule-induced trinucleotide repeat contractions during <i>in vitro</i> DNA synthesis2021

    • Author(s)
      Dohno Chikara、Hagihara Masaki、Binti Mohd Zaifuddin Nursakinah、Nihei Mizuki、Saito Kaoru、Nakatani Kazuhiko
    • Journal Title

      Chemical Communications

      Volume: 57 Issue: 26 Pages: 3235-3238

    • DOI

      10.1039/d1cc00349f

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Rational design of a photoswitchable DNA glue enabling high regulatory function and supramolecular chirality transfer2021

    • Author(s)
      Simeth Nadja A.、Kobayashi Shotaro、Kobauri Piermichele、Crespi Stefano、Szymanski Wiktor、Nakatani Kazuhiko、Dohno Chikara、Feringa Ben L.
    • Journal Title

      Chemical Science

      Volume: 12 Issue: 26 Pages: 9207-9220

    • DOI

      10.1039/d1sc02194j

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A small-molecule fluorescence probe ANP77 for sensing RNA internal loop of C, U and A/CC motifs and their binding molecules2021

    • Author(s)
      Das Bimolendu、Murata Asako、Nakatani Kazuhiko
    • Journal Title

      Nucleic Acids Research

      Volume: 49 Issue: 15 Pages: 8462-8470

    • DOI

      10.1093/nar/gkab650

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cyclic mismatch binding ligands interact with disease-associated CGG trinucleotide repeats in RNA and suppress their translation2021

    • Author(s)
      Konieczny Patryk、Mukherjee Sanjukta、Stepniak-Konieczna Ewa、Taylor Katarzyna、Niewiadomska Daria、Piasecka Agnieszka、Walczak Agnieszka、Baud Anna、Dohno Chikara、Nakatani Kazuhiko、Sobczak Krzysztof
    • Journal Title

      Nucleic Acids Research

      Volume: 49 Issue: 16 Pages: 9479-9495

    • DOI

      10.1093/nar/gkab669

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Short Tandem Repeat Contractions during In Vitro DNA Synthesis by Repeat-binding Molecules2021

    • Author(s)
      Hagihara Masaki、Dohno Chikara、Saito Kaoru、Sugimoto Kazuhiro、Hishinuma Yuta、Sohma Yuri、Shibata Tomonori、Nakatani Kazuhiko
    • Journal Title

      Chemistry Letters

      Volume: 50 Issue: 11 Pages: 1848-1851

    • DOI

      10.1246/cl.210415

    • NAID

      130008113718

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] FAN1 exo- not endo-nuclease pausing on disease-associated slipped-DNA repeats: A mechanism of repeat instability2021

    • Author(s)
      Deshmukh Amit Laxmikant、Caron Marie-Christine、Mohiuddin Mohiuddin、Lanni Stella、Panigrahi Gagan B.、Khan Mahreen、Engchuan Worrawat、Shum Natalie、Faruqui Aisha、Wang Peixiang、Yuen Ryan K.C.、Nakamori Masayuki、Nakatani Kazuhiko、Masson Jean-Yves、Pearson Christopher E.
    • Journal Title

      Cell Reports

      Volume: 37 Issue: 10 Pages: 110078-110078

    • DOI

      10.1016/j.celrep.2021.110078

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Small molecule targeting r(UGGAA)n disrupts RNA foci and alleviates disease phenotype in Drosophila model2021

    • Author(s)
      Shibata Tomonori、Nagano Konami、Ueyama Morio、Ninomiya Kensuke、Hirose Tetsuro、Nagai Yoshitaka、Ishikawa Kinya、Kawai Gota、Nakatani Kazuhiko
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 1-13

    • DOI

      10.1038/s41467-020-20487-4

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The dimeric form of 1, 3 - diaminoisoquinoline derivative rescued the mis - splicing of Atp2a1 and Clcn1 genes in myotonic dystrophy type 1 mouse model2020

    • Author(s)
      Matsumoto, J. ; Nakamori, M. ; Okamoto, T. ; Murata, A. ; Dohno, C. ; Nakatani, K.
    • Journal Title

      Chem. Eur. J.

      Volume: 26 Issue: 63 Pages: 14305-14309

    • DOI

      10.1002/chem.202001572

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Chemical Probing of Thymine in the TGG/CGG Triad to Explore the Deamination of 5-Methylcytosine in the CGG Repeat2020

    • Author(s)
      Yagi Yuki、Yamada Takeshi、Nakatani Kazuhiko
    • Journal Title

      Biochemistry

      Volume: 59 Issue: 29 Pages: 2679-2683

    • DOI

      10.1021/acs.biochem.0c00333

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed

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Published: 2019-04-18   Modified: 2024-01-30  

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