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Dynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry
http://hdl.handle.net/10069/0002000434
http://hdl.handle.net/10069/0002000434fda6a299-6dfa-486e-a686-28c22aeb7813
名前 / ファイル | ライセンス | アクション |
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Item type | 学術雑誌論文 / Journal Article(1) | |||||||||||||||||||||||||||
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公開日 | 2023-12-12 | |||||||||||||||||||||||||||
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言語 | en | |||||||||||||||||||||||||||
タイトル | Dynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry | |||||||||||||||||||||||||||
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言語 | eng | |||||||||||||||||||||||||||
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資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||||||||||||||||||||||||
資源タイプ | journal article | |||||||||||||||||||||||||||
著者 |
Terada, Chisato
× Terada, Chisato
× Oh, Kaho
× Tsubaki, Ryutaro
× Chan, Bun
× Aibara, Nozomi
× Ohyama, Kaname
× Shibata, Masa-Aki
× Wada, Takehiko
× Harada-Shiba, Mariko
× Yamayoshi, Asako
× Yamamoto, Tsuyoshi
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内容記述タイプ | Abstract | |||||||||||||||||||||||||||
内容記述 | 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. | |||||||||||||||||||||||||||
言語 | en | |||||||||||||||||||||||||||
書誌情報 |
en : Nature Communications 巻 14, 号 1, p. art. no. 7972, 発行日 2023-12-02 |
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言語 | en | |||||||||||||||||||||||||||
出版者 | Springer Nature | |||||||||||||||||||||||||||
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収録物識別子タイプ | EISSN | |||||||||||||||||||||||||||
収録物識別子 | 2041-1723 | |||||||||||||||||||||||||||
DOI | ||||||||||||||||||||||||||||
関連タイプ | isIdenticalTo | |||||||||||||||||||||||||||
識別子タイプ | DOI | |||||||||||||||||||||||||||
関連識別子 | 10.1038/s41467-023-43714-0 | |||||||||||||||||||||||||||
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言語 | en | |||||||||||||||||||||||||||
権利情報 | 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 | |||||||||||||||||||||||||||
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出版タイプ | VoR | |||||||||||||||||||||||||||
出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||||||||||||||||||||||||
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内容記述タイプ | Other | |||||||||||||||||||||||||||
内容記述 | Nature Communications, 14(1), art. no. 7972; 2023 | |||||||||||||||||||||||||||
言語 | en |