一覧に戻る

タイトル
  • en Dynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry
作成者
    • en Terada, Chisato
    • en Oh, Kaho
    • en Tsubaki, Ryutaro
    • en Chan, Bun
    • en Aibara, Nozomi
    • en Ohyama, Kaname
    • en Shibata, Masa-Aki
    • en Wada, Takehiko
    • en Harada-Shiba, Mariko
    • en Yamayoshi, Asako
    • en Yamamoto, Tsuyoshi
権利情報
  • en This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. © The Author(s) 2023
内容注記
  • Abstract en Off-target interactions between antisense oligonucleotides (ASOs) with stateof-the-art modifications and biological components still pose clinical safety liabilities. Tomitigate a broad spectrumof off-target interactions and enhance the safety profile of ASO drugs, we here devise a nanoarchitecture named BRace On a THERapeutic aSo (BROTHERS or BRO), which is composed of a standard gapmer ASO paired with a partially complementary peptide nucleic acid (PNA) strand. We show that these non-canonical ASO/PNA hybrids have reduced non-specific protein-binding capacity. The optimization of the structural and thermodynamic characteristics of this duplex system enables the operation of an in vivo toehold-mediated strand displacement (TMSD) reaction, effectively reducing hybridization with RNA off-targets. The optimized BROs dramatically mitigate hepatotoxicity while maintaining the ontarget knockdown activity of their parent ASOs in vivo. This technique not only introduces a BRO class of drugs that could have a transformative impact on the extrahepatic delivery of ASOs, but can also help uncover the toxicity mechanism of ASOs.
  • Other en Nature Communications, 14(1), art. no. 7972; 2023
出版者 en Springer Nature
日付
    Issued2023-12-02
言語
  • eng
資源タイプ journal article
出版タイプ VoR
資源識別子 HDL http://hdl.handle.net/10069/0002000434 , URI https://nagasaki-u.repo.nii.ac.jp/records/2000434
関連
  • isIdenticalTo DOI https://doi.org/10.1038/s41467-023-43714-0
収録誌情報
    • EISSN 2041-1723
      • en Nature Communications
      • 巻14 号1 開始ページart. no. 7972
ファイル
コンテンツ更新日時 2023-12-14