Development of artificial nucleoside analogues for the duplex DNA recognition, and antigene oligonucleotides

2022 Fiscal Year Final Research Report

• Project/Area Number: 19H03351
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: Kyushu University
• Principal Investigator: Taniguchi Yosuke 九州大学, 薬学研究院, 准教授 (00452714)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 核酸医薬 / 創薬化学 / ゲノム創薬 / 核送達技術 / アンチジーン核酸

Outline of Final Research Achievements

In the development of functional oligonucleotides, we found that guard oligonucleotides incorporating multiple 2’-deoxyuridines (dUs) can release antigene oligonucleotides in the nucleus, and that the introduction of this duplex DNA formation system has a stronger antigene effect. Furthermore, we found that its can be multiconjugated with functional molecules. Therefore, the foundation for the development of functional oligonucleotides was established. In the development of artificial nucleoside analogues for the formation of non-natural type triplex DNA, we succeeded in developing a new 5-methyl-CG base pair recognition molecule, and found that it can expand the triplex DNA forming sequences and inhibit the activity of demethylase, TET enzyme. Furthermore, the newly chemically synthesized PNA units were successfully found to bind to duplex DNA having CpG sequences by melting temperature measurement.

Free Research Field

核酸化学

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は、新規モダリティ創薬の一つとして期待される核酸医薬のなかでも、これまでに標的をされていない2本鎖DNAを直接標的とした新規創薬手法の基盤構築に関する革新的な成果を挙げており、社会的な意義は大きい。特に、核酸の高次構造の一つである3本鎖DNA形成を人工的に形成させることに着目した人工核酸の化学合成にも成功し、遺伝子発現のエピジェネティック制御にも関わっている5メチルCG塩基対の認識にも成功し認識配列の拡張に成功している。さらに、アンチジーン機能を効率的に働かせるための細胞内さらには核内導入法を新規に明らかしており、学術的な意義も非常に大きい。