Development of modified nucleic acid possessing RNase H activity for antisense oligonucleotides without phosphorothioate (PS) modification

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K05716
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 37010:Bio-related chemistry
• Research Institution: Tokushima Bunri University
• Principal Investigator: Hari Yoshiyuki 徳島文理大学, 薬学部, 教授 (50347423)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: アンチセンス核酸 / 修飾オリゴ核酸

Outline of Final Research Achievements

Phosphorothioate (PS) modifications are generally used for antisense oligonucleotides (ASOs). In particular, the gap region of RNase H-dependent ASOs consists of natural nucleosides to need to be recognized by RNase H; thus, PS modifications are necessary for the gap region. In this study, development of a nucleic acid analog that works as a substrate of RNase H was tried aiming to remove PS modification from the gap region in ASOs. Oligonucleotides containing nucleic acid analogs possessing carboxylic acid equivalents at the 4' position, 4'-methylthio group, and bridge structure between 1' and 4' positions were synthesized and their RNase H activity was examined. Some analogs that can lead to partial removal of PS modifications could be found.

Free Research Field

核酸有機化学

Academic Significance and Societal Importance of the Research Achievements

アンチセンス核酸医薬品に利用されるホスホロチオエート（PS）修飾は毒性や品質管理の面での問題を抱えている。そのような中、本研究の成果はアンチセンス核酸のPS修飾の数を減らすことにつながり、これら課題の緩和が期待できる。また、本成果は、全くPS修飾する必要のないアンチセンス核酸の開発を将来実現するために有用な知見をもたらすと考えられる。以上のことから、本研究成果は、今後のアンチセンス核酸をはじめとするオリゴ核酸医薬品開発の発展に貢献することが期待できる。