Antisense oligonucleotides (ASOs) are becoming a promising class of drugs for treating various diseases. Over the past few decades, many modified nucleic acids have been developed for application to ASOs, aiming to enhance their duplex-forming ability toward cognate mRNA and improve their stability against enzymatic degradations. Modulating the sugar conformation of nucleic acids by substituting an electron-withdrawing group at the 2′-position or incorporating a 2′,4′-bridging structure is a common approach for enhancing duplex-forming ability. Here, we report on incorporating an N-tert-butylguanidinium group at the 2′,4′-bridging structure, which greatly enhances duplex-forming ability because of its interactions with the minor groove. Our results indicated that hydrophobic substituents fitting the grooves of duplexes also have great potential to increase duplex-forming ability.

中文翻译：

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N-叔丁基胍-或N-叔丁基-N'-甲基胍桥核酸修饰的寡核苷酸具有极高双链体形成能力的机制

反义寡核苷酸（ASO）正在成为治疗各种疾病的一类有前途的药物。在过去的几十年里，许多修饰的核酸被开发用于 ASO，旨在增强它们对同源 mRNA 的双链体形成能力，并提高它们对抗酶促降解的稳定性。通过在2'位取代吸电子基团或掺入2',4'-桥接结构来调节核酸的糖构象是增强双链体形成能力的常见方法。在这里，我们报道了在 2',4'-桥接结构上引入 N-叔丁基胍基团，由于其与小沟的相互作用，大大增强了双链体形成能力。我们的结果表明，适合双链体凹槽的疏水取代基也具有增加双链体形成能力的巨大潜力。