反义寡核苷酸：从设计到治疗应用

Antisense oligonucleotides: from design to therapeutic application.

Chan Jasmine H P, Lim Shuhui, Wong W S Fred

Department of Pharmacology, Yong Loo Lin School of Medicine and Immunology Program, National University of Singapore, Singapore.

Clin Exp Pharmacol Physiol. 2006 May-Jun;33(5-6):533-40. doi: 10.1111/j.1440-1681.2006.04403.x.

Abstract

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.

摘要

反义寡核苷酸（ASO）是一段短链脱氧核糖核苷酸类似物，它通过沃森-克里克碱基配对以序列特异性方式与互补mRNA杂交。ASO-mRNA异源双链体的形成要么触发核糖核酸酶H活性，导致mRNA降解，要么通过空间位阻核糖体活性诱导翻译停滞，通过抑制剪接干扰mRNA成熟，或者使细胞核中的前体mRNA不稳定，从而导致靶蛋白表达下调。2. ASO不仅是蛋白质靶点鉴定和验证中有用的实验工具，也是针对蛋白质表达失调疾病的高度选择性治疗策略。3. 在本综述中，我们讨论了ASO合理设计的各种理论方法、ASO的化学修饰、ASO递送系统以及ASO相关毒理学。最后，我们调查了当前各种临床研究中的ASO药物。