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Development of the New Recognition Molecules of DNA Sequences Based on the GC- and AT-Selective Ligands

Research Project

Project/Area Number 11672105
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Chemical pharmacy
Research InstitutionKYUSHU UNIVERSITY

Principal Investigator

SASAKI Shigeki  KYUSHU UNIVERSITY, FACULTY OF PHARMACEUTICAL SCIENCES, ASSOCIATE PROFESSOR, 薬学研究院, 助教授 (10170672)

Co-Investigator(Kenkyū-buntansha) NAGATSUGI Fumi  Graduate School of Pharmacetical Sciences, KYUSHU UNIVERSITY Assistant Professor, 薬学研究院, 助手 (90208025)
TORIGOE Hidetaka  RIKEN, Researcher, ジーンバンク室, 研究員 (80227678)
OHISHI Hirofumi  Osaka College of Pharmacy, Assistant Professor, 情報科学解析センター, 助手 (00211095)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1999: ¥2,500,000 (Direct Cost: ¥2,500,000)
KeywordsCOMBINATORIAL CHEMISTRY / SOLID-STATE LIBRARY / PEPTIDE LIBRARY / DUPLEX DNA / DNA-BINDING MOLECULES / HYDROPHOBIC AMINO ACIDS / DNA結合
Research Abstract

Development of methodology for specific inhibition of gene expression has become of major interest recently, because of great potential of therapeutic application. We expected to develope new ligands toward target DNA sequences. Furthermore, useful information for design of sequence selective ligands would be obtained by structural analysis of binding between the new ligands and the target DNA.
In the conceptual mechanism, a primary process of the ligand-binding includes a hydrophobic transfer from an aqueous solution to the DNA minor groove. At this step, the shape of the ligand isohelical with the curvature of the groove is an important factor of the binding. Similar to oligo-tetrahydrofuran compounds that have been shown to take a helix-like conformation, bisTHF compounds with long alkyl chains take a crescent shape as the stable conformation. An MM calculation has indicated that they might fit well in the minor groove. In order to check this hypothesis, we synthesized a variety of new molecules with a diamino-bisTHF structure as the common skeleton. The amino groups were introduced to make a compound soluble in water and to gain some electrostatic binding forces.
In conclusion, we have discovered new DNA-binding molecules based on a diamino-bisTHF skeleton. From the fundamental investigation with UV melting curve, ethidium displacement assay and the ITC measurement, selective binding affinity of RR8 to GC pairs with high affinity has become apparent. It has been also clearly shown that both the stereochemistry of the amino groups and the alkyl chain length play major roles for the DNA binding. Footprinting analyses with DNase I has revealed that a GCGC site is the most matched site for RR8 in the sequence studied here. Although the detailed binding mode of RR8 is not yet clear, GC-preference of the new binding motif will provide useful information for the design of new binding molecules for GC-rich sequence.

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (25 results)

All Other

All Publications (25 results)

  • [Publications] F.Nagatsugi,D.Usui,T.Kawasaki,M.Maeda,S.Sasaki: "Selective Reaction to a Flipping Cytidine of the Duplex DNA Mediated by Triple Helix Formation,"Bioorg & Med.Chem Lett. 11. 343-345 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Sasaki,T.Kanda,N.Ishibashi,F.Yamamoto,T.Haradahira,T.Okauchi,J.Maeda,K.Suzuki,M.Maeda: "4, 5, 9, 10-Tetrahydro-1, 4-Ethanobenz [b] quinolizine as a Prodrug for Its Quninolizinium Cation as a Ligand to the Open State of the TCP-Binding Site of NMDA Receptors"Bioorg & Med.Chem Lett. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Sasaki,T.Ehara,I.Sakata,Y.Fujino,N.Harada,J.Kimura,H.Nakamura,M.Maeda: "Development of Novel Telomerase Inhibitors Based on a Bisndole Unit,"Bioorg & Med.Chem Lett.,. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Sasaki,T.Shibata,H.Torigoe,Y.Shibata,M.Maeda: "Novel Class of DNA Binding Motifs Based on Bistetrahydrofuran and Bisfuran Skeleton with Long Alkyl Chains"Nucleoside & Nucleotides. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Sasaki: "Active Oligonucleotides Incorporating Alkylating Agent as Potential Sequence-and Base Selective Modifier of Gene Expression,"Eur.J.Phar.Sci.,. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Alam,Md.Rowshon,Maeda,Minoru,Sasaki,Shigeki: "DNA-Binding Peptides Searched from the Solid-Phase Combinatorial Library with the Use of the Magnetic Beads Attaching the Target Duplex DNA,"Bioorg & Med.Chem. 8. 465-473 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Sasaki, T.Shibata, H.Torigoe, Y.Shibata, M.Maeda: "Novel Class of DNA Binding Motifs Based on Bistetrahydrofuran and Bisfuran Skeleton with Long Alkyl Chains"Nucleoside & Nucleotides. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] F.Nagatsugi, D.Usui, T.Kawasaki, M.Maeda, S.Sasaki: "Selective Reaction to a Flipping Cytidine of the Duplex DNA Mediated by Triple Helix Formation"Bioorg & Med.Chem Lett. 11. 343-345 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Sasaki, T.Kanda, N.Ishibashi, F.Yamamoto, T.Haradahira, T.Okauchi, J.Maeda, K.Suzuki, M.Maeda: "4, 5, 9, 10-Tetrahydro-1, 4-Ethanobenz [b] quinolizine as a Prodrug for Its Quninolizinium Cation as a Ligand to the Open State of the TCP-Binding Site of NMDA Receptors"Bioorg & Med.Chem Lett. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Sasaki, T.Ehara, I.Sakata, Y.Fujino, N.Harada, J.Kimura, H.Nakamura, M.Maeda: "Development of Novel Telomerase Inhibitors Based on a Bisndole Unit"Bioorg & Med.Chem Lett. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Sasaki: "Active Oligonucleotides Incorporating Alkylating Agent as Potential Sequence- and Base Selective Modifier of Gene Expression"Eur.J.Phar.Sci.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Alam, Md.Rowshon ; Maeda, Minoru ; Sasaki, Shigeki: "DNA-Binding Peptides Searched from the Solid-Phase Combinatorial Library with the Use of the Magnetic Beads Attaching the Target Duplex DNA"Bioorg & Med.Chem.. 8. 465-473 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] F.Nagatsugi,D.Usui,T.Kawasaki,M.Maeda,S.Sasaki: "Selective Reaction to a Flipping Cytidine of the Duplex DNA Mediated by Triple Helix Formation,"Bioorg & Med.Chem Lett. 11. 343-345 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] S.Sasaki,T.Kanda,N.Ishibashi,F.Yamamoto,T.Haradahira,T.Okauchi,J.Maeda,K.Suzuki,M.Maeda: "4,5,9,10-Tetrahydro-1,4-Ethanobenz [b] quinolizine as a Prodrug for Its Quninolizinium Cation as a Ligand to the Open State of the TCP-Binding Site of NMDA Receptors"Bioorg & Med.Chem Lett. (印刷中).

    • Related Report
      2000 Annual Research Report
  • [Publications] S.Sasaki,T.Ehara,I.Sakata,Y.Fujino,N.Harada,J.Kimura,H.Nakamura,M.Maeda: "Development of Novel Telomerase Inhibitors Based on a Bisndole Unit,"Bioorg & Med.Chem Lett.,. (印刷中).

    • Related Report
      2000 Annual Research Report
  • [Publications] S.Sasaki,T.Shibata,H.Torigoe,Y.Shibata,M.Maeda: "Novel Class of DNA Binding Motifs Based on Bistetrahydrofuran and Bisfuran Skeleton with Long Alkyl Chains"Nucleoside & Nucleotides. (印刷中).

    • Related Report
      2000 Annual Research Report
  • [Publications] S.Sasaki: "Active Oligonucleotides Incorporating Alkylating Agent as Potential Sequence- and Base Selective Modifier of Gene Expression,"Eur.J.Phar.Sci... (印刷中).

    • Related Report
      2000 Annual Research Report
  • [Publications] Alam,Md.Rowshon;Maeda,Minoru;Sasaki,Shigeki: "DNA-Binding Peptides Searched from the Solid-Phase Combinatorial Library with the Use of the Magnetic Beads Attaching the Target Duplex DNA,"Bioorg & Med.Chem. 8. 465-473 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Alam,Md.Rowshon;Maeda,Minoru;Sasaki,Shigeki: "DNA-Binding Peptides Searched from the Solid-Phase Combinatorial Library with the Use of the Magnetic Beads Attaching the Target Duplex"Bioorg&Med.Chem.. 8. 1-12 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nagatsugi,F.;Kawasaki,T.;Usui,D.;Maeda,M.,Sasaki,S.: "Highly Efficient and Selective Cross-Linking to Cytidine Based on the New Strategy for Auto-Activation within"J.Amer.Chem.Soc.. 121. 6753-6754 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Matsuura,N.;Yashiki,Y.;Nakashima,S.;Maeda,M.;Sasaki,Shigeki: "Shortcut Stereoselective Synthesis of 1-b-Alkyl-2-Deoxyribose Derivatives via Witting-Horner-Emons Reaction"Heterocycles. 51(5). 975-978 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Shibata,T.;Torigoe,H.;Shibata,Y.;Maeda,M.;Sasaki,Shigeki: "Novel DNA-Binding Ligands with Sequence Selectivity Based on Hydrophobic Structure"Nucleic Acids,Symp.Ser.,. 42. 251-252 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Alam,Md.Rowshon;Maeda,Minoru;Sasaki,Shigeki: "DNA Binding Affinity of Pentapeptides Selected from Combinatorial Library"Nucleic Acids,Symp.Ser.,. 42. 173-174 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sasaki,Shigeki: "Active Oligonucleotides Incorporating Alkylating Agent as Potential Sequence-and Base Selective Modifier of Gene"Eur.J.Phar.Sci.. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] 佐々木茂貴: "薬学におけるラジオアイソトープ・放射線、第5章標識化合物の合成"本間義夫、前田稔編集:広川書店. 14 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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