2000 Fiscal Year Final Research Report Summary
Development of the New Recognition Molecules of DNA Sequences Based on the GC- and AT-Selective Ligands
| Project/Area Number |
11672105
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Chemical pharmacy
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
SASAKI Shigeki KYUSHU UNIVERSITY, FACULTY OF PHARMACEUTICAL SCIENCES, ASSOCIATE PROFESSOR, 薬学研究院, 助教授 (10170672)
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| 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)
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| Project Period (FY) |
1999 – 2000
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| Keywords | COMBINATORIAL CHEMISTRY / SOLID-STATE LIBRARY / PEPTIDE LIBRARY / DUPLEX DNA / DNA-BINDING MOLECULES / HYDROPHOBIC AMINO ACIDS / DNA結合 |
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| 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.
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[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
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[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
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