Development of ANCsome contaning aASO-RNaseH conjugates

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K05307
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 37030:Chemical biology-related
• Research Institution: Kyoto Institute of Technology
• Principal Investigator: KOBORI AKIO 京都工芸繊維大学, 分子化学系, 教授 (00397605)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: アンチセンス / 核酸医薬 / 光反応

Outline of Final Research Achievements

In this research period, we succeeded in developing two types of nucleic acid derivatives (1) and (2) that selectively form covalent bonds with target proteins that have the ability to bind to nucleic acids under light irradiation and in a molecularly crowded environment. Nucleic acid derivative (1) : By using oligonucleic acid derivatives with a diazirine moiety at the 5' end, RNaseH-ASO complexes were successfully constructed with high efficiency and sequence selectivity. Nucleic acid derivative (2) : we newly developed photoresponsive cross-linking nucleotides with a chloraldehyde derivative protected by a nitrobenzyl group at the 3' end. By using the oligonucleotides, the activity of telomerase, which is highly expressed in cancer cells and the highly important target protein for anticancer reagents, were selectively inhibited using light irradiation as a trigger under molecularly crowded environment.

Free Research Field

核酸化学

Academic Significance and Societal Importance of the Research Achievements

本研究期間において我々は、光照射下かつ分子狭雑環境下において、標的タンパク質と選択的に共有結合を形成する2種類の核酸誘導体の開発に成功した。開発した2種類のオリゴ核酸は標的タンパクに結合している核酸を配列選択的に認識しながら、標的タンパク質表面のアミノ酸残基と光照射をトリガーとして化学結合を形成する性質を持つことから、タンパク質を標的とした核酸医薬として、これまでに報告されていない核酸医薬の新しいプラットフォームを提供する結果が得られたと考えている。今後は、得られた光架橋核酸-タンパク質共有結合体の解析を行うとともに、光架橋性核酸を利用したタンパク質活性阻害法の汎用性について検討する。