Development of artificial ribonucleases
Development of artificial ribonucleases
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DOI：
10.1351/pac199870010111
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发表时间：
1998-01-01
影响因子：
1.8
通讯作者：
Husken, D
中科院分区：
文献类型：
--
作者：
Haner, R;Hall, J;Husken, D
反义寡核苷酸通过在mRNA水平上干扰蛋白质表达，提供了一种治疗遗传疾病的新方法。第一代硫代磷酸反义寡核苷酸在动物实验中显示出有希望的结果，并且目前正在临床上测试几种化合物对多种疾病的作用。然而，该技术的各个方面的改进，如稳定性、寡核苷酸的长度和靶亲和力的减少，仍然是高度期望的。因此，在过去的十年中，已经报道了大量的反义化合物的化学修饰。然而，与硫代磷酸酯不同，大多数第二代修饰不通过基于RNase H的机制诱导信使RNA的降解，这在大多数情况下是反义活性的必要组分。能够降解mRNA的替代方法包括将RNA切割基团共价连接至修饰的寡核苷酸。大环镧系元素配合物与修饰的反义寡核苷酸组合可用于特异性切割mRNA。这种人工核糖核酸酶的制备，性质和使用的突出。特别地，描述了切割具有多次翻转的RNA的构建体的设计和制备。
Antisense oligonucleotides offer a new way of treating genetically based diseases by interfering with protein expression on the mRNA level. First generation phosphorothioate antisense oligonucleotides have shown promising results in animal experiments and several compounds are currently being tested in the clinics against a variety of diseases. Nevertheless, improvements of various aspects of the technology, such as stability, reduction of length and target affinity of oligonucleotides, are still highly desirable. As a consequence, a large number of chemical modifications of antisense compounds has been reported during the last decade. Unlike phosphorothioates, however, most second generation modifications do not induce degradation of messenger RNA by an RNase H-based mechanism, which is in most cases an essential component of antisense activity. An alternative approach to enable degradation of the mRNA comprises the covalent attachment of RNA cleaving groups to modified oligonucleotides. Macrocyclic lanthanide complexes, in combination with modified antisense oligonucleotides, can be used to specifically cleave mRNA. The preparation, properties and use of such artificial ribonucleases are highlighted. In particular, the design and preparation of constructs cleaving RNA with multiple turn-over is described.