Development of potent chemically modified siRNAs that suppress HCV replication

• Project/Area Number: 21590114
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Gifu University
• Principal Investigator: UENO Yoshihito 岐阜大学, 応用生物科学部, 准教授 (20250467)
• Co-Investigator(Renkei-kenkyūsha): KOHARA Michinori 東京都医学研究機構, 東京都臨床医学総合研究所, 参事研究員 (10250218)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: RNA干渉 / 抗ウイルス剤 / RNA / siRNA / DNA / 遺伝子 / ノックダウン / 肝炎ウイルス / 治療 / 核酸 / RNAi / miRNA / oligonucleotide / HCV / virus

Research Abstract

Small interfering RNA(siRNA) is a non-coding RNA with considerable potential as a new therapeutic drug for intractable diseases. siRNAs can be rationally designed and synthesized if the sequences of the disease-causing genes are known. In this study, we found that incorporation of naphthalene biaryl unit at the 5' and 3' ends of sense and antisense strands of siRNA improves silencing activity and nuclease resistance. Further, we found that the modified siRNA suppressed HCV replication more efficiently than unmodified siRNA. Thus, the naphthalene biaryl modification may hold promise as a method for improvement of the silencing activity and nuclease-resistance of siRNAs.

Research Products

• [Journal Article] Incorporation of biaryl units into the 5' and 3' ends of sense and antisense strands of siRNA duplexes improves strand selectivity and nuclease resistance (2011)
  • Author(s): Yoshikawa, K., Ogata, A., Matsuda, C., Kohara, M., Iba, H., Kitade, Y. and Ueno, Y.
  • Journal Title: Bioconjugate Chem. Volume: 22 Issue: 1 Pages: 42-49
  • DOI: 10.1021/bc100301w
  • Peer Reviewed
• [Journal Article] Biaryl modification of the 5′-terminus of one strand of a microRNA duplex induces strand specificity (2010)
  • Author(s): Ogata, A., Furukawa, C., Sakurai, K., Iba, H., Kitade, Y. and Ueno, Y.
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 20 Pages: 7299-7302
  • URL: http://dx.doi.org/10.1016/j.bmcl.2010.10.077
  • Peer Reviewed
• [Journal Article] Diazirine-containing RNA photocrosslinking probes for the study of siRNA-protein interactions (2010)
  • Author(s): Kuboe, S., Yoda, M., Ogata, A., Kitade, Y., Tomari, Y. and Ueno, Y.
  • Journal Title: ChemCom Volume: 46 Issue: 39 Pages: 7367-7369
  • DOI: 10.1039/c0cc02450c
  • Peer Reviewed
• [Journal Article] Synthesis of nuclease-resistant siRNAs possessing universal overhangs (2009)
  • Author(s): Ueno, Y., Watanabe, Y., Shibata, A., Yoshikawa, K., Takano, T., Kohara, M. and Kitade, Y.
  • Journal Title: Bioorg. Med. Chem. Volume: 17 Pages: 1974-1981
  • URL: http://dx.doi.org/10.1016/j.bmc.2009.01.033
  • Peer Reviewed
• [Journal Article] Effect of incorporation of alkyl linkers into siRNAs on RNA interference (2009)
  • Author(s): Ueno, Y., Yoshikawa, K., Kitamura, Y. and Kitade, Y.
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 19 Pages: 875-877
  • URL: http://dx.doi.org/10.1016/j.bmcl.2008.11.107
  • Peer Reviewed
• [Journal Article] Synthesis of nuclease-resistant siRNAs possessing universal overhangs (2009)
  • Author(s): Yoshihito Ueno
  • Journal Title: Bioorg.Med.Chem. 17 Pages: 1974-1981
  • Peer Reviewed
• [Journal Article] (2009)
  • Author(s): Yoshihito Ueno
  • Journal Title: Bioorg.Med.Chem.Lett. 19 Pages: 875-877
  • Peer Reviewed
• [Presentation] 5'-末端にインターカレーターを導入した機能性siRNAの合成と遺伝子発現抑制効果 (2011)
  • Author(s): 上野義仁
  • Organizer: アンチセンス・遺伝子・デリバリーシンポジウム
  • Place of Presentation: 大阪大学コンベンションセンター
  • Year and Date: 2011-09-01
• [Presentation] 芳香族化合物で修飾した安定で有用なRNA分子の開発 (2010)
  • Author(s): 上野義仁
  • Organizer: 日本化学会第90春季年会
  • Place of Presentation: 東大阪市
  • Year and Date: 2010-03-27
• [Presentation] SYNTHESIS AND PROPERTIES OF SIRNAS MODIFIED WITH AROMATIC COMPOUNDS (2009)
  • Author(s): Y. Ueno
  • Organizer: Joint Symposium of the 5th Annual Meeting of the Oligonucleotide Therapeutics Society and 19th Antisense Symposium
  • Place of Presentation: Fukuoka
  • Year and Date: 2009-11-04
• [Presentation] SYNTHESIS OF 5'-CAPPED SIRNA FOR SUPPRESSION OF OFF-TARGET EFFECTS AND ITS CAPABILITY TO ACHIEVE PROTEIN EXPRESSION (2009)
  • Author(s): A. Ogata, Y. Ueno, C. Furukawa, K. Sakurai, H. Iba, Y. Kitamura, and Y. Kitade
  • Organizer: Joint Symposium of the 5th Annual Meeting of the Oligonucleotide Therapeutics Society and 19th Antisense Symposium
  • Place of Presentation: Fukuoka
  • Year and Date: 2009-11-04
• [Presentation] DIAZIRINE-CONTAINING RNA PHOTO-CROSS-LINKING PROBES FOR THE STUDY OF SIRNA-PROTEIN INTERACTIONS, S. Kuboe (2009)
  • Author(s): M. Yoda, Y. Ueno, Y. Tomari, Y. Kitamura, and Y. Kitade
  • Organizer: Joint Symposium of the 5th Annual Meeting of the Oligonucleotide Therapeutics Society and 19th Antisense Symposium
  • Place of Presentation: Fukuoka
  • Year and Date: 2009-11-04
• [Presentation] EFFECT OF INCORPORATION OF AROMATIC COMPOUNDS INTO DANGLING ENDS OF SIRNAS (2009)
  • Author(s): K. Yoshikawa, Y. Kitamura, Y. Ueno, and Y. Kitade
  • Organizer: Joint Symposium of the 5th Annual Meeting of the Oligonucleotide Therapeutics Society and 19th Antisense Symposium
  • Place of Presentation: Fukuoka
  • Year and Date: 2009-11-04