Bridged Nucleic Acids for Therapeutic Oligonucleotides

Islam, Md Ariful; Obika, Satoshi

doi:10.1007/978-981-16-1313-5_18-1

Cited by 1 publication

(1 citation statement)

References 85 publications

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“…ASO therapeutics generally incorporate sugar-modified nucleotides that increase in thermodynamic stability, render nuclease resistance, and improve pharmacokinetic/pharmacodynamic profiles 2 – 4 . Examples of sugar-modified nucleotides include 2′-modification analogs—such as 2′- O -methyl (2′-OMe) and 2′- O -methoxyethyl (2′-MOE)—and 2′,4′-bridged nucleic acid (BNA) analogs 5 —such as locked nucleic acid (LNA) 6 , 7 and 2′- O ,4′- C -ethylene-bridged nucleic acid (ENA) 8 .…”

Section: Introductionmentioning

confidence: 99%

Introduction of sugar-modified nucleotides into CpG-containing antisense oligonucleotides inhibits TLR9 activation

Yoshida,

Hagihara,

Uchida

et al. 2024

Sci Rep

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Antisense oligonucleotides (ASOs) are synthetic single-stranded oligonucleotides that bind to RNAs through Watson–Crick base pairings. They are actively being developed as therapeutics for various human diseases. ASOs containing unmethylated deoxycytidylyl-deoxyguanosine dinucleotide (CpG) motifs are known to trigger innate immune responses via interaction with toll-like receptor 9 (TLR9). However, the TLR9-stimulatory properties of ASOs, specifically those with lengths equal to or less than 20 nucleotides, phosphorothioate linkages, and the presence and arrangement of sugar-modified nucleotides—crucial elements for ASO therapeutics under development—have not been thoroughly investigated. In this study, we first established SY-ODN18, an 18-nucleotide phosphorothioate oligodeoxynucleotide with sufficient TLR9-stimulatory activity. We demonstrated that an unmethylated CpG motif near its 5′-end was indispensable for TLR9 activation. Moreover, by utilizing various sugar-modified nucleotides, we systematically generated model ASOs, including gapmer, mixmer, and fully modified designs, in accordance with the structures of ASO therapeutics. Our results illustrated that introducing sugar-modified nucleotides in such designs significantly reduces TLR9-stimulatory activity, even without methylation of CpG motifs. These findings would be useful for drug designs on several types of ASOs.

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