Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA.
Biochem Pharmacol. 2021 Jul;189:114196. doi: 10.1016/j.bcp.2020.114196. Epub 2020 Aug 13.
When coined, the term "antisense" included oligonucleotides of any structure, with any chemical modification and designed to work through any post-RNA hybridization mechanism. However, in practice the term "antisense" has been used to describe single stranded oligonucleotides (ss ASOs) designed to hybridize to RNAswhile the term "siRNA" has come to mean double stranded oligonucleotides designed to activate Ago2. However, the two approaches share many common features. The medicinal chemistry developed for ASOs greatly facilitated the development of siRNA technology and remains the chemical basis for both approaches. Many of challenges faced and solutions achieved share many common features. In fact, because ss ASOs can be designed to activate Ago2, the two approaches intersect at this remarkably important protein. There are also meaningful differences. The pharmacokinetic properties are quite different and thus potential routes of delivery differ. ASOs may be designedto use a variety of post-RNA binding mechanismswhile siRNAs depend solely on the robust activity of Ago2. However, siRNAs and ASOs are both used for therapeutic purposes and both must be and can be understood in a pharmacological context. Thus, the goals of this review are to put ASOs in pharmacological context and compare their behavior as pharmacological agents to the those of siRNAs.
术语“反义”最初包含任何结构、任何化学修饰的寡核苷酸，并设计通过任何 RNA 杂交后的机制发挥作用。然而，在实践中，术语“反义”已被用于描述设计为与 RNA 杂交的单链寡核苷酸（ss ASO），而术语“siRNA”已逐渐表示设计用于激活 Ago2 的双链寡核苷酸。然而，这两种方法有许多共同的特征。为 ASO 开发的药物化学极大地促进了 siRNA 技术的发展，并且仍然是这两种方法的化学基础。所面临的许多挑战和所取得的解决方案具有许多共同的特征。事实上，由于 ss ASO 可以设计为激活 Ago2，因此这两种方法在这个非常重要的蛋白质上相交。也有明显的差异。药代动力学特性有很大不同，因此潜在的给药途径也不同。ASO 可以设计为使用多种 RNA 结合后的机制，而 siRNA 仅依赖于 Ago2 的强大活性。然而，siRNA 和 ASO 都被用于治疗目的，都必须并且可以在药理学背景下理解。因此，本综述的目的是将 ASO 置于药理学背景下，并将其作为药理学药物的行为与 siRNA 的行为进行比较。
