Saleh Amer F, Arzumanov Andrey A, Gait Michael J
Laboratory of Molecular Biology, Medical Research Council, Cambridge, UK.
Methods Mol Biol. 2012;867:365-78. doi: 10.1007/978-1-61779-767-5_23.
The chemistry of the oligonucleotide backbone is crucial to obtaining high activity in vivo in exon skipping applications. Apart from the ability to bind strongly and sequence-specifically to pre-mRNA targets, the type of backbone also influences cell delivery, in vivo pharmacology, bio-distribution, toxicology, and ultimately the therapeutic use in humans. Reviewed here are classes of oligonucleotide commonly used for exon skipping applications, namely negatively charged backbones typified by RNA analogues having 2'-O-substitution and a phosphorothioate linkage and charge-neutral backbones such as PNA and PMO. Also discussed are peptide conjugates of PNA and PMO that enhance cellular and in vivo delivery and their potential for drug development. Finally, the prospects for development of other analogue types in exon skipping applications are outlined.
在外显子跳跃应用中，寡核苷酸骨架的化学性质对于在体内获得高活性至关重要。除了能够与前体mRNA靶标进行强结合和序列特异性结合外，骨架类型还会影响细胞递送、体内药理学、生物分布、毒理学，最终影响其在人类中的治疗用途。本文综述了常用于外显子跳跃应用的寡核苷酸类别，即以具有2'-O-取代和硫代磷酸酯键的RNA类似物为代表的带负电荷骨架以及诸如肽核酸（PNA）和吗啉代寡核苷酸（PMO）等电荷中性骨架。还讨论了增强细胞和体内递送的PNA和PMO的肽缀合物及其在药物开发中的潜力。最后，概述了在外显子跳跃应用中开发其他类似物类型的前景。
