Dynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry.

Autor: Terada C; Department of Chemistry of Biofunctional Molecules, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.; JSPS Research Fellow (DC1), Japan Society for the Promotion of Science, Tokyo, Japan., Oh K; Department of Chemistry of Biofunctional Molecules, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan., Tsubaki R; Department of Chemistry of Biofunctional Molecules, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan., Chan B; Graduate School of Engineering, Nagasaki University, Nagasaki, Japan., Aibara N; Department of Pharmacy Practice, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan., Ohyama K; Department of Molecular Pathochemistry, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan., Shibata MA; Department of Anatomy and Cell Biology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Japan., Wada T; Institute of Multidisciplinary Research for Advanced Materials (IMRAM), Tohoku University, Sendai, Miyagi, Japan., Harada-Shiba M; Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan.; Cardiovascular Center, Osaka Medical and Pharmaceutical University, Takatsuki, Japan., Yamayoshi A; Department of Chemistry of Biofunctional Molecules, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan., Yamamoto T; Department of Chemistry of Biofunctional Molecules, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan. tsuyoshi.yamamoto@nagasaki-u.ac.jp.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Dec 02; Vol. 14 (1), pp. 7972. Date of Electronic Publication: 2023 Dec 02.
DOI: 10.1038/s41467-023-43714-0
Abstrakt: Off-target interactions between antisense oligonucleotides (ASOs) with state-of-the-art modifications and biological components still pose clinical safety liabilities. To mitigate a broad spectrum of 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 on-target 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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