Synthesis of novel anti-HIV nucleosides aiming at overcoming drug resistance and its application to nucleic acid medicines

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06552
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: Tohoku Medical and Pharmaceutical University
• Principal Investigator: Yoshimura Yuichi 東北医科薬科大学, 薬学部, 教授 (00230813)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: ヌクレオシド / 核酸医薬 / 4'-チオヌクレオシド

Outline of Final Research Achievements

In order to satisfy both the creation of nucleoside units applicable to nucleic acid medicines and the development of antiviral drugs, it is necessary to design based on an ordinary nucleoside skeleton having primary and secondary hydroxy groups in appropriate positions in its molecule. In this study, we designed 4'-substituted 4'-thionucleosides and dihydrothiopyrano-nucleosides as derivatives that satisfy this condition, and studied their synthesis. In particular, 4'-thio LNA/BNA was also designed as a promising nucleoside monomer unit for nucleic acid medicines, and its synthesis was achieved.

Free Research Field

医薬品化学

Academic Significance and Societal Importance of the Research Achievements

抗体医薬については多くの医薬品が上市されているのに比べ、核酸医薬はまだ大きく遅れを取っている。その理由として、核酸医薬が抱えている問題点があり、１）ターゲットDNAやRNAへの特異的結合と二重鎖の形成並びにオフターゲット効果の抑制、２）ヌクレアーゼなどの核酸代謝酵素に対する抵抗性の獲得、３）核酸医薬の組織・細胞移行性の改善、４）インターフェロン応答による自然免疫活性化の回避などが挙げられる。報告者が開発した4'-チオLNA/BNAモノマーはRNAに対する親和性を維持しつつ、導入したオリゴマーのヌクレアーゼに対する抵抗性の改善が期待され、血中でより安定な核酸医薬の開発へとつながるものである。