Development of prodrug-type siRNA with long term activities

• Project/Area Number: 15K21517
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Physical pharmacy; Chemical pharmacy
• Research Institution: Osaka University of Pharmaceutical Sciences
• Principal Investigator: Hayashi Junsuke 大阪薬科大学, 薬学部, 助手(移行) (30740295)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 核酸医薬 / siRNA / プロドラッグ / ジスルフィド / グルタチオン

Outline of Final Research Achievements

We have developed novel prodrug-type siRNAs containing 2'-O-methyldithiomethyl groups which responsive to intracellular reducing environment and transformable into natural 2'-OH RNA. The gene silencing effects of 2'-O-methyldithiomethyl (MDTM)-modified siRNAs were remarkably stronger than those of natural(2'-OH) siRNAs. Furthermore, the siRNA activities of 2'-O-MDTM-siRNA were enhanced by increasing of 2’-O-MDTM modifications.

Research Products

• [Journal Article] Syntheses of prodrug-type phosphotriester oligonucleotides responsive to intracellular reducing environment for improvement of cell membrane permeability and nuclease resistance (2017)
  • Author(s): Junsuke Hayashi, Yusuke Samezawa, Yosuke Ochi, Shun-ichi Wada, Hidehito Urata
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: in press Issue: 14 Pages: 3135-3138
  • DOI: 10.1016/j.bmcl.2017.05.031
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Gene silencing by 2′-O-methyldithiomethyl-modified siRNA, a prodrug-type siRNA responsive to reducing environment (2016)
  • Author(s): Yosuke Ochi, Mieko Imai, Osamu Nakagawa, Junsuke Hayashi, Shun-ichi Wada, Hidehito Urata
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 26 Issue: 3 Pages: 845-848
  • DOI: 10.1016/j.bmcl.2015.12.074
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 細胞内還元環境下で応答するプロドラッグ型リン酸トリエステル-オリゴ核酸の開発 (2017)
  • Author(s): 林 淳祐, 鮫澤佑介, 和田俊一, 浦田秀仁
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 東北大学
  • Year and Date: 2017-03-24
• [Presentation] 細胞内還元環境で活性化するプロドラッグ型 siRNAの RNAi 活性の経時変化 (2017)
  • Author(s): 西垣美沙, 越智 洋輔, 林 淳祐, 和田 俊一, 浦田 秀仁
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 東北大学
  • Year and Date: 2017-03-24
• [Presentation] 細胞内還元環境において活性化する新規プロドラッグ型siRNA (REDUCT-siRNA) の2’-O-methyldithiomethy修飾がRNA干渉能に与える影響 (2016)
  • Author(s): 林 淳祐, 西垣美沙, 越智洋輔, 和田俊一, 浦田秀仁
  • Organizer: 日本核酸医薬学会第2回年会
  • Place of Presentation: 東京理科大学
  • Year and Date: 2016-11-15
• [Presentation] 細胞内還元環境に応答する2’-プロドラッグ型RNA (REDUCT-RNA) の開発 ―核酸医薬への応用を指向したRNA干渉作用に関する検討― (2016)
  • Author(s): 林 淳祐、越智洋輔、和田俊一、浦田秀仁
  • Organizer: 第 66 回 日本薬学会近畿支部総会・大会
  • Place of Presentation: 大阪薬科大学
  • Year and Date: 2016-10-15