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Shorter Is Better: The α-(l)-Threofuranosyl Nucleic Acid Modification Improves Stability, Potency, Safety, and Ago2 Binding and Mitigates Off-Target Effects of Small Interfering RNAs
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2023-08-28 , DOI: 10.1021/jacs.3c04744 Shigeo Matsuda 1 , Saikat Bala 2 , Jen-Yu Liao 2 , Dhrubajyoti Datta 1 , Atsushi Mikami 1 , Lauren Woods 1 , Joel M Harp 3 , Jason A Gilbert 1 , Anna Bisbe 1 , Rajar M Manoharan 1 , MaryBeth Kim 1 , Christopher S Theile 1 , Dale C Guenther 1 , Yongfeng Jiang 1 , Saket Agarwal 1 , Rajanikanth Maganti 1 , Mark K Schlegel 1 , Ivan Zlatev 1 , Klaus Charisse 1 , Kallanthottathil G Rajeev 1 , Adam Castoreno 1 , Martin Maier 1 , Maja M Janas 1 , Martin Egli 3 , John C Chaput 2 , Muthiah Manoharan 1
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2023-08-28 , DOI: 10.1021/jacs.3c04744 Shigeo Matsuda 1 , Saikat Bala 2 , Jen-Yu Liao 2 , Dhrubajyoti Datta 1 , Atsushi Mikami 1 , Lauren Woods 1 , Joel M Harp 3 , Jason A Gilbert 1 , Anna Bisbe 1 , Rajar M Manoharan 1 , MaryBeth Kim 1 , Christopher S Theile 1 , Dale C Guenther 1 , Yongfeng Jiang 1 , Saket Agarwal 1 , Rajanikanth Maganti 1 , Mark K Schlegel 1 , Ivan Zlatev 1 , Klaus Charisse 1 , Kallanthottathil G Rajeev 1 , Adam Castoreno 1 , Martin Maier 1 , Maja M Janas 1 , Martin Egli 3 , John C Chaput 2 , Muthiah Manoharan 1
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Chemical modifications are necessary to ensure the metabolic stability and efficacy of oligonucleotide-based therapeutics. Here, we describe analyses of the α-(l)-threofuranosyl nucleic acid (TNA) modification, which has a shorter 3′–2′ internucleotide linkage than the natural DNA and RNA, in the context of small interfering RNAs (siRNAs). The TNA modification enhanced nuclease resistance more than 2′-O-methyl or 2′-fluoro ribose modifications. TNA-containing siRNAs were prepared as triantennary N-acetylgalactosamine conjugates and were tested in cultured cells and mice. With the exceptions of position 2 of the antisense strand and position 11 of the sense strand, the TNA modification did not inhibit the activity of the RNA interference machinery. In a rat toxicology study, TNA placed at position 7 of the antisense strand of the siRNA mitigated off-target effects, likely due to the decrease in the thermodynamic binding affinity relative to the 2′-O-methyl residue. Analysis of the crystal structure of an RNA octamer with a single TNA on each strand showed that the tetrose sugar adopts a C4′-exo pucker. Computational models of siRNA antisense strands containing TNA bound to Argonaute 2 suggest that TNA is well accommodated in the region kinked by the enzyme. The combined data indicate that the TNA nucleotides are promising modifications expected to increase the potency, duration of action, and safety of siRNAs.
中文翻译：
越短越好：α-(l)-苏呋喃糖基核酸修饰可提高稳定性、效力、安全性和 Ago2 结合并减轻小干扰 RNA 的脱靶效应
为了确保基于寡核苷酸的治疗的代谢稳定性和功效，化学修饰是必要的。在这里，我们描述了在小干扰 RNA (siRNA) 的背景下对 α-(l)-苏呋喃糖基核酸 (TNA) 修饰的分析，该修饰具有比天然 DNA 和 RNA 更短的 3'-2' 核苷酸间连接。TNA 修饰比 2'- O-甲基或 2'-氟核糖修饰增强了核酸酶抗性。将含有 TNA 的 siRNA 制备为三触角N-乙酰半乳糖胺缀合物，并在培养细胞和小鼠中进行测试。除了反义链的位置 2 和有义链的位置 11 之外，TNA 修饰不会抑制 RNA 干扰机制的活性。在一项大鼠毒理学研究中，TNA 置于 siRNA 反义链的第 7 位可减轻脱靶效应，这可能是由于相对于 2'- O-甲基残基的热力学结合亲和力降低。对每条链上具有单个 TNA 的 RNA 八聚体的晶体结构分析表明，丁糖采用 C4'-外折叠。含有与 Argonaute 2 结合的 TNA 的 siRNA 反义链的计算模型表明，TNA 很好地容纳在由酶扭结的区域中。综合数据表明，TNA 核苷酸是有前途的修饰，有望提高 siRNA 的效力、作用持续时间和安全性。
更新日期：2023-08-28
中文翻译：
越短越好：α-(l)-苏呋喃糖基核酸修饰可提高稳定性、效力、安全性和 Ago2 结合并减轻小干扰 RNA 的脱靶效应
为了确保基于寡核苷酸的治疗的代谢稳定性和功效，化学修饰是必要的。在这里，我们描述了在小干扰 RNA (siRNA) 的背景下对 α-(l)-苏呋喃糖基核酸 (TNA) 修饰的分析，该修饰具有比天然 DNA 和 RNA 更短的 3'-2' 核苷酸间连接。TNA 修饰比 2'- O-甲基或 2'-氟核糖修饰增强了核酸酶抗性。将含有 TNA 的 siRNA 制备为三触角N-乙酰半乳糖胺缀合物，并在培养细胞和小鼠中进行测试。除了反义链的位置 2 和有义链的位置 11 之外，TNA 修饰不会抑制 RNA 干扰机制的活性。在一项大鼠毒理学研究中，TNA 置于 siRNA 反义链的第 7 位可减轻脱靶效应，这可能是由于相对于 2'- O-甲基残基的热力学结合亲和力降低。对每条链上具有单个 TNA 的 RNA 八聚体的晶体结构分析表明，丁糖采用 C4'-外折叠。含有与 Argonaute 2 结合的 TNA 的 siRNA 反义链的计算模型表明，TNA 很好地容纳在由酶扭结的区域中。综合数据表明，TNA 核苷酸是有前途的修饰，有望提高 siRNA 的效力、作用持续时间和安全性。
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