Antisense drug discovery and development technology considered in a pharmacological context
Antisense drug discovery and development technology considered in a pharmacological context
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DOI：
10.1016/j.bcp.2020.114196
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发表时间：
2021-06-04
影响因子：
5.8
通讯作者：
Geary, Richard S.
中科院分区：
文献类型：
--
作者：
Crooke, Stanley T.;Liang, Xue-hai;Geary, Richard S.
当被创造时，术语“反义”包括具有任何结构的寡核苷酸，具有任何化学修饰并且被设计为通过任何RNA后杂交机制起作用。然而，在实践中，术语“反义”已用于描述设计成与RNA杂交的单链寡核苷酸（ss ASO），而术语“siRNA”已变为意指设计成激活Ago2的双链寡核苷酸。然而，这两种方法有许多共同的特点。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实现的解决办法具有许多共同特点。事实上，因为ss ASO可以被设计成激活Ago2，所以这两种方法在这个非常重要的蛋白质上交叉。也有一些有意义的差异。药代动力学性质差异很大，因此潜在的递送途径不同。ASO可以被设计成使用多种RNA后结合机制，而siRNA仅依赖于Ago2的稳健活性。然而，siRNA和ASO都用于治疗目的，并且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，并将其作为药理学试剂的行为与siRNA的行为进行比较。
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 RNAs while 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 designed to use a variety of post-RNA binding mechanisms while 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.