Development of artificial nucleic acid aptamers to improve the efficacy of antisense oligonucleotide

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K14743
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 37010:Bio-related chemistry
• Research Institution: National Institutes of Biomedical Innovation, Health and Nutrition
• Principal Investigator: Kasahara Yuuya 国立研究開発法人医薬基盤・健康・栄養研究所, 医薬基盤研究所 創薬デザイン研究センター, 副センター長 (10740673)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: アプタマー / SELEX / ポリメラーゼ / 人工核酸

Outline of Final Research Achievements

The objective of this study was to create aptamers that could be used as delivery carriers. To this end, libraries with improved functions were created using artificial nucleic acids and screened based on their functions. Dual-modified artificial nucleic acid triphosphates were synthesized by modifying a methoxy group at the 2' position of the sugar moiety of the nucleic acid to enhance nuclease stability and an indole ring at the 5-position of the uracil base via a linker to facilitate intracellular translocation. Subsequently, the conditions for efficient library production were identified by refining each reaction condition during enzyme synthesis. In addition, artificial nucleic acid aptamers with improved blood-brain barrier (BBB) permeability were successfully obtained by screening using an in vitro BBB model.

Free Research Field

核酸化学

Academic Significance and Societal Importance of the Research Achievements

本研究を通して、人工核酸を搭載したライブラリの効率的な酵素合成方法の確立と、機能に着目したスクリーニングによるデリバリー担体としての機能を有したアプタマーの効率的な取得方法を確立することができた。本研究成果は、従来の天然のDNAやRNAで構成されたアプタマーを生体内で利用する際の最大の課題である核酸分解酵素に対する安定性を解決することにつながるため、学術的意義は大きい。今後は、本研究で得られた知見をいかして様々な機能を有した人工核酸アプタマーの創出に応用展開していく予定である。