Inorganic Mimics of Ribonucleases and Ribozymes: From Random Cleavage to Sequence-Specific Chemistry to Catalytic Antisense Drugs.
Inorganic Mimics of Ribonucleases and Ribozymes: From Random Cleavage to Sequence-Specific Chemistry to Catalytic Antisense Drugs.
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DOI：
10.1021/cr960422k
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发表时间：
1998-04
期刊：
影响因子：
62.1
通讯作者：
B. Trawick;A. Daniher;J. Bashkin
中科院分区：
文献类型：
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作者：
B. Trawick;A. Daniher;J. Bashkin
对核酶和核糖核酸酶的功能模拟物的兴趣是由各种科学和医学目标驱动的。在给出了几个工作定义、假设和前提的简短介绍之后，对这些目标进行了描述和解释。然后介绍了基于金属的 RNA 切割策略，并与其他方法（包括生物方法和纯有机方法）进行了对比。 Oivanen、Kuusela 和 Lönnberg 的姊妹篇文章对有机方法进行了详尽的讨论。我们描述了核酶模拟物的演变，从早期、非特异性、不明确（但高度活性）的催化剂（源自“缓冲液中的游离金属离子”），到保留 RNA 裂解活性的明确金属复合物的出现。 1, 2 此类金属配合物使得该领域的中心前提得以测试，并最终证明了可以通过合成模拟物实现 RNA 序列特异性切割的概念。我们解释了化学、生物化学和分子生物学的不断融合如何帮助塑造该领域的研究，从早期模拟物的分子设计到筛选 RNA 酯交换催化剂的分析方法的选择。对这些分析方法进行了严格的评估。出于本综述的目的，核酶和核糖核酸酶的功能模拟物被定义为“使用仿生化学反应（例如酯交换和水解）以序列定向方式切割 RNA 的合成分子”。为简单起见，我们将使用术语“核酶模拟物”来表示这些化合物。由于多种原因，酯交换反应和水解反应被归为“亲核裂解反应”（方案 1）。这些反应与各自采用的对磷 (V) 的亲核攻击密切相关。 Perreault 和 Anslyn 最近发表的一篇论文巧妙地统一了这些反应之间的机械联系。 3 对于酯交换反应，醇或醇盐是亲核试剂，而对于水解反应，水或氢氧化物几乎总是亲核试剂。 4, 5 此外，大多数催化 RNA 酯交换反应的无机试剂继续将所得的 2', 3'-环状单磷酸酯水解为 2'- 和 3'-磷酸单酯的混合物，如方案 1b 所示。
Interest in functional mimics of ribozymes and ribonucleases is driven by a variety of scientific and medical goals. After a brief introduction, in which several working definitions, postulates and premises are given, these goals are described and explained. Metal-based strategies for RNA cleavage are then presented and contrasted with other approaches, including biological and purely organic methods. The organic methods are exhaustively discussed in a companion article by Oivanen, Kuusela, and Lönnberg. We describe the evolution of ribozyme mimics from early, nonspecific, ill-defined (but highly active) catalysts that were derived from “free metal ions in buffer”, to the advent of well-defined metal complexes that retained RNA cleavage activity. 1, 2 Such metal complexes allowed the central premise of this area to be tested and eventually led to proof of the concept that sequence-specific cleavage of RNA can be achieved by synthetic mimics. We explain how the continuing convergence of chemistry, biochemistry, and molecular biology have helped shape research in this area, from the molecular design of early mimics to the choice of analytical methods for the screening of RNA transesterification catalysts. A critical assessment of these analytical approaches is provided.For the purpose of this review, functional mimics of ribozymes and ribonucleases are defined as “synthetic molecules that cleave RNA in a sequencedirected manner, using biomimetic chemical reactions such as transesterification and hydrolysis”. For simplicity, we will use the term “ribozyme mimics” to represent these compounds. The transesterification and hydrolysis reactions are grouped together as “nucleophilic cleavage reactions” for several reasons (Scheme 1). These reactions are closely related by the nucleophilic attack on phosphorus (V) that each employs. The mechanistic connection between these reactions was elegantly unified in a recent paper by Perreault and Anslyn. 3 For transesterification, an alcohol or alkoxide is the nucleophile, while for hydrolysis, water or hydroxide is almost always the nucleophile. 4, 5 Furthermore, most inorganic reagents that catalyze RNA transesterification go on to hydrolyze the resulting 2′, 3′-cyclic monophosphate to a mixture of 2′-and 3′-phosphate monoesters, as indicated in Scheme 1b.