Molecular design strategy to avoid side effects of covalent drugs

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K21249
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 37:Biomolecular chemistry and related fields
• Research Institution: Nagoya University
• Principal Investigator: Kimura Yasuaki 名古屋大学, 理学研究科, 講師 (80769977)
• Co-Investigator(Kenkyū-buntansha): 村上 努 国立感染症研究所, エイズ研究センター, 主任研究官 (50336385)
• Project Period (FY): 2020-07-30 – 2022-03-31
• Keywords: 共有結合医薬 / 核酸アナログ / ポリメラーゼ / 阻害剤 / リン酸プロドラッグ

Outline of Final Research Achievements

Mechanistic analysis and structure-activity relationship studies of a reverse transcriptase inhibitor with a novel mechanism of action were conducted. In the mechanistic analysis, we verified the release of reactive species associated with the enzymatic reaction unique to this inhibitor and the inhibitory effect based on the release of reactive species. In the structure-activity relationship study, we found a molecular design guideline for further enhancement of activity and succeeded in developing a highly effective prodrug of phosphate-based on a novel chemical structure

Free Research Field

医薬化学

Academic Significance and Societal Importance of the Research Achievements

新規作用機序を有する核酸アナログ系ポリメラーゼ阻害剤の開発において、阻害機構の解明で得られた反応性の知見、および反応性活性種の構造と阻害活性の相関情報は、類似メカニズムを有する活性型共有結合性阻害剤の開発に有用な知見を与えるものである。また新規構造に基づくリン酸プロドラッグの創出についても、核酸アナログに留まらず幅広い応用展開の可能性を有し、リン酸基含有の医薬開発に有用な手法を提示したと考えられる。