Development of covalent drugs activatable by the target enzymes

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K14356
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 37030:Chemical biology-related
• Research Institution: Nagoya University
• Principal Investigator: Kimura Yasuaki 名古屋大学, 理学研究科, 助教 (80769977)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: 共有結合医薬 / 標的選択制 / 抗ウイルス薬 / 抗ガン薬 / 核酸誘導体

Outline of Final Research Achievements

A covalent drug is a drug molecule that forms a covalent bond with a target enzyme to inhibit its function, and has high inhibitory activity. Due to this property, covalent drugs targeting various enzymes have been developed in recent years. However, covalent drugs often form covalent bonds with non-targeting proteins, and side effects derived from them are a major issue in the development of covalent drugs. In this research, as a strategy to avoid such side effect problems, we developed a covalent drug that is activated by a target enzyme and developed an antiviral drug by using a nucleoside analog as an example. The developed nucleoside analog showed good pharmacological activity against HIV.

Free Research Field

生体関連化学

Academic Significance and Societal Importance of the Research Achievements

昨今のコロナウイルス感染症拡大でも明らかになった通り、新規の作用機序と強力な薬理活性を有する抗ウイルス薬の開発は、社会的にも重要な課題である。本研究では一般的に強力な活性を有する共有結合医薬の範疇で、新規の作用機序を有する抗ウイルス薬の開発を行った。医薬開発戦略の特徴は、医薬分子が標的とする酵素に作用した際に初めて、共有結合医薬としての反応性を獲得する点にある。開発した核酸アナログはエイズウイルス(HIV)に対して良好な薬理活性を示した。今後さらなる分子最適化を通じ、さまざま抗ウイルス薬開発に適用可能な方法論としての確立を目指す。