Dynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry
抄録
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.
Nature Communications, 14(1), art. no. 7972; 2023
収録刊行物
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- Nature Communications
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Nature Communications 14 (1), art. no. 7972-, 2023-12-02
Springer Nature
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詳細情報 詳細情報について
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- CRID
- 1050016991318309888
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- ISSN
- 20411723
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- HANDLE
- 10069/0002000434
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- 本文言語コード
- en
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- 資料種別
- journal article
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- データソース種別
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- IRDB