Antisense oligonucleotides: From design to therapeutic application
Antisense oligonucleotides: From design to therapeutic application
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DOI：
10.1111/j.1440-1681.2006.04403.x
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发表时间：
2006-05-01
影响因子：
2.9
通讯作者：
Wong, WSF
中科院分区：
文献类型：
--
作者：
Chan, JHP;Lim, SH;Wong, WSF
1. 反义寡核苷酸（ASO）是一种短链脱氧核糖核苷酸类似物，通过沃森-克里克碱基配对以序列特异性的方式与互补的mRNA杂交。ASO-mRNA异双工的形成或触发RNase H活性，导致mRNA降解，或通过核糖体活性的位阻诱导翻译阻滞，或通过抑制剪接干扰mRNA成熟，或破坏细胞核中pre-mRNA的稳定，导致靶蛋白表达下调2。ASO不仅是蛋白质靶点鉴定和验证的有用实验工具，而且是一种高度选择性的治疗蛋白质表达异常疾病的策略。本文就ASO的合理设计、ASO的化学修饰、ASO给药系统和ASO相关毒理学等方面的理论研究进行了综述。最后，我们综述了目前临床研究中ASO药物的情况。
1. An antisense oligonucleotide (ASO) is a short strand of deoxyribonucleotide analogue that hybridizes with the complementary mRNA in a sequence-specific manner via Watson-Crick base pairing. Formation of the ASO-mRNA heteroduplex either triggers RNase H activity, leading to mRNA degradation, induces translational arrest by steric hindrance of ribosomal activity, interferes with mRNA maturation by inhibiting splicing or destabilizes pre-mRNA in the nucleus, resulting in downregulation of target protein expression.2. The ASO is not only a useful experimental tool in protein target identification and validation, but also a highly selective therapeutic strategy for diseases with dysregulated protein expression.3. In the present review, we discuss various theoretical approaches to rational design of ASO, chemical modifications of ASO, ASO delivery systems and ASO-related toxicology. Finally, we survey ASO drugs in various current clinical studies.