Cycloalkane Incorporation Into the 2′,4′-Bridge of Locked Nucleic Acid: Enhancing Nuclease Stability, Reducing Phosphorothioate Modifications, and Lowering Hepatotoxicity in Antisense Oligonucleotides

Yamaguchi, Takao; Komine, Hibiki; Sugiura, Takaya; Kumagai, Riku; Yoshida, Tokuyuki; Sasaki, Kiyomi; Nakayama, Taisuke; Kamada, Haruhiko; Inoue, Takao; Obika, Satoshi

doi:https://doi.org/10.1021/jacsau.5c01005

Cycloalkane Incorporation Into the 2′,4′-Bridge of Locked Nucleic Acid: Enhancing Nuclease Stability, Reducing Phosphorothioate Modifications, and Lowering Hepatotoxicity in Antisense Oligonucleotides

Yamaguchi, Takao; Komine, Hibiki; Sugiura, Takaya et al.

JACS Au, 2025, 5(10), 5111-5120

アクセス数:57件（2026-02-15 22:59 集計）

固定URL: https://hdl.handle.net/11094/103677

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タイトル	Cycloalkane Incorporation Into the 2′,4′-Bridge of Locked Nucleic Acid: Enhancing Nuclease Stability, Reducing Phosphorothioate Modifications, and Lowering Hepatotoxicity in Antisense Oligonucleotides
著者	NRID 1000080596601 1000080596601 ORCID 0000-0003-3180-0257 0000-0003-3180-0257 researchmap permalink takao-yamaguchi takao-yamaguchi Scopus Author ID 56322895500 56322895500 著者名 Yamaguchi, Takao
	著者名 Komine, Hibiki
	著者名 Sugiura, Takaya
	著者名 Kumagai, Riku
	NRID 1000000649387 1000000649387 著者名 Yoshida, Tokuyuki
	NRID 1000000773136 1000000773136 著者名 Sasaki, Kiyomi
	NRID 1000090467598 1000090467598 著者名 Nakayama, Taisuke
	NRID 1000000324509 1000000324509 著者名 Kamada, Haruhiko
	NRID 1000050361605 1000050361605 著者名 Inoue, Takao
	NRID 1000080243252 1000080243252 ORCID 0000-0002-6842-6812 0000-0002-6842-6812 researchmap permalink read0014368 read0014368 Scopus Author ID 7003800550 7003800550 著者名 Obika, Satoshi
キーワード等	antisense oligonucleotides
	bridged nucleic acids
	cycloalkanes
	gapmer
	hepatotoxicity
	locked nucleic acid (LNA)
	nuclease stability
	phosphorothioate reduction
内容	Yamaguchi T., Komine H., Sugiura T., et al. Cycloalkane Incorporation Into the 2′,4′-Bridge of Locked Nucleic Acid: Enhancing Nuclease Stability, Reducing Phosphorothioate Modifications, and Lowering Hepatotoxicity in Antisense Oligonucleotides. JACS Au 5, 5111 (2025); https://doi.org/10.1021/jacsau.5c01005.
抄録	2′-O,4′-C-Methylene-bridged nucleic acid (2′,4′-BNA), also known as locked nucleic acid (LNA), is widely used to modify antisense oligonucleotides (ASOs) because it significantly enhances their ability to form duplexes with target RNAs, thereby boosting ASO activity. However, 2′,4′-BNA/LNA exhibits only moderate nuclease stability, necessitating additional modifications, such as phosphorothioate (PS) linkages. Our previous studies demonstrated that oligonucleotides modified with 2′-O,4′-C-spirocyclopropylene-bridged nucleic acid (scpBNA) retain duplex-forming abilities similar to those of 2′,4′-BNA/LNA, while showing significantly improved nuclease stability. In the present study, we introduce 2′-O,4′-C-spirocyclopentylene-bridged nucleic acid (scpBNA2), which offers even greater nuclease stability than scpBNA. We synthesized scpBNA2 phosphoramidites containing either thymine or 5-methylcytosine nucleobases and incorporated them into gapmer-type ASOs. Both scpBNA- and scpBNA2-modified ASOs exhibited antisense activity comparable to that of their 2′,4′-BNA/LNA-modified counterparts, maintaining activity even with reduced PS modifications in the scpBNA- or scpBNA2-modified regions. Furthermore, hepatotoxicity observed with 2′,4′-BNA/LNA-modified ASOs was significantly reduced when 2′,4′-BNA/LNA was replaced with either scpBNA or scpBNA2. Overall, these findings underscore the potential of scpBNA and scpBNA2 for use in therapeutic ASOs.
出版者	American Chemical Society
収録物名	JACS Au
巻(号)	5(10)
ページ	5111-5120
刊行年月	2025-10-15
言語	英語
ハンドルURL	https://hdl.handle.net/11094/103677
eISSN	26913704
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1021/jacsau.5c01005
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCMI資源タイプ	text
DCTERMS.bibliographicCitation	JACS Au. 2025, 5(10), p. 5111-5120
DC.title	Cycloalkane Incorporation Into the 2′,4′-Bridge of Locked Nucleic Acid: Enhancing Nuclease Stability, Reducing Phosphorothioate Modifications, and Lowering Hepatotoxicity in Antisense Oligonucleotides
DC.creator	Yamaguchi, Takao
	Komine, Hibiki
	Sugiura, Takaya
	Kumagai, Riku
	Yoshida, Tokuyuki
	Sasaki, Kiyomi
	Nakayama, Taisuke
	Kamada, Haruhiko
	Inoue, Takao
	Obika, Satoshi
DC.publisher	American Chemical Society
DC.language' scheme='DCTERMS.RFC1766	英語
DC.type' scheme='DCTERMS.DCMIType	text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-10-15
DC.identifier	https://doi.org/10.1021/jacsau.5c01005
DC.subject	antisense oligonucleotides
	bridged nucleic acids
	cycloalkanes
	gapmer
	hepatotoxicity
	locked nucleic acid (LNA)
	nuclease stability
	phosphorothioate reduction
DC.description	Yamaguchi T., Komine H., Sugiura T., et al. Cycloalkane Incorporation Into the 2′,4′-Bridge of Locked Nucleic Acid: Enhancing Nuclease Stability, Reducing Phosphorothioate Modifications, and Lowering Hepatotoxicity in Antisense Oligonucleotides. JACS Au 5, 5111 (2025); https://doi.org/10.1021/jacsau.5c01005.
DCTERMS.abstract	2′-O,4′-C-Methylene-bridged nucleic acid (2′,4′-BNA), also known as locked nucleic acid (LNA), is widely used to modify antisense oligonucleotides (ASOs) because it significantly enhances their ability to form duplexes with target RNAs, thereby boosting ASO activity. However, 2′,4′-BNA/LNA exhibits only moderate nuclease stability, necessitating additional modifications, such as phosphorothioate (PS) linkages. Our previous studies demonstrated that oligonucleotides modified with 2′-O,4′-C-spirocyclopropylene-bridged nucleic acid (scpBNA) retain duplex-forming abilities similar to those of 2′,4′-BNA/LNA, while showing significantly improved nuclease stability. In the present study, we introduce 2′-O,4′-C-spirocyclopentylene-bridged nucleic acid (scpBNA2), which offers even greater nuclease stability than scpBNA. We synthesized scpBNA2 phosphoramidites containing either thymine or 5-methylcytosine nucleobases and incorporated them into gapmer-type ASOs. Both scpBNA- and scpBNA2-modified ASOs exhibited antisense activity comparable to that of their 2′,4′-BNA/LNA-modified counterparts, maintaining activity even with reduced PS modifications in the scpBNA- or scpBNA2-modified regions. Furthermore, hepatotoxicity observed with 2′,4′-BNA/LNA-modified ASOs was significantly reduced when 2′,4′-BNA/LNA was replaced with either scpBNA or scpBNA2. Overall, these findings underscore the potential of scpBNA and scpBNA2 for use in therapeutic ASOs.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	103677
citation_title	Cycloalkane Incorporation Into the 2′,4′-Bridge of Locked Nucleic Acid: Enhancing Nuclease Stability, Reducing Phosphorothioate Modifications, and Lowering Hepatotoxicity in Antisense Oligonucleotides
citation_author	Yamaguchi, Takao
	Komine, Hibiki
	Sugiura, Takaya
	Kumagai, Riku
	Yoshida, Tokuyuki
	Sasaki, Kiyomi
	Nakayama, Taisuke
	Kamada, Haruhiko
	Inoue, Takao
	Obika, Satoshi
citation_publisher	American Chemical Society
citation_language	英語
citation_date	2025-10-15
citation_journal_title	JACS Au
citation_volume	5
citation_issue	10
citation_firstpage	5111
citation_lastpage	5120
citation_doi	https://doi.org/10.1021/jacsau.5c01005
citation_public_url	https://hdl.handle.net/11094/103677

Cycloalkane Incorporation Into the 2′,4′-Bridge of Locked Nucleic Acid: Enhancing Nuclease Stability, Reducing Phosphorothioate Modifications, and Lowering Hepatotoxicity in Antisense Oligonucleotides

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