Passioura Toby, Suga Hiroaki
Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Bunkyo-ku, Tokyo 113-0033, Japan.
Chem Commun (Camb). 2017 Feb 7;53(12):1931-1940. doi: 10.1039/c6cc06951g.
Studies of the fundamental nature of RNA catalysis and the potential mechanism of a shift from the "RNA world" to proteinaceous life lead us to identify a set of ribozymes (flexizymes) capable of promiscuous tRNA acylation. Whilst theoretically and mechanistically interesting in their own right, flexizymes have turned out to have immense practical value for the simple synthesis of tRNAs acylated with unusual amino acids, which in turn can be used for the ribosomal synthesis of peptides containing non-canonical residues. Using this technique, it is possible to synthesise peptides containing a range of structural features (macrocyclic backbones, backbone N-methylation, d-stereochemistry, etc.) commonly observed in natural product secondary metabolites, a chemical class that has historically been a rich source of drug-like molecules. Moreover, when combined with biochemical display screening technologies, this synthetic approach can be used to generate (and screen for target affinity) extremely diverse (in excess of 10 compound) chemical libraries, making it an extraordinary tool for drug discovery. The current review charts the history of flexizyme technology and its use for non-canonical peptide synthesis and screening.
对RNA催化的基本性质以及从“RNA世界”向蛋白质生命转变的潜在机制的研究，使我们鉴定出一组能够进行混杂tRNA酰化的核酶（柔性酶）。柔性酶本身在理论和机制上很有趣，但事实证明，它们对于简单合成用非常规氨基酸酰化的tRNA具有巨大的实用价值，而这些酰化的tRNA又可用于核糖体合成含有非经典残基的肽。利用这项技术，可以合成含有一系列在天然产物次级代谢产物中常见的结构特征（大环骨架、骨架N-甲基化、d-立体化学等）的肽，天然产物次级代谢产物这一化学类别历来是类药物分子的丰富来源。此外，当与生化展示筛选技术相结合时，这种合成方法可用于生成（并筛选靶标亲和力）极其多样（超过10种化合物）的化学文库，使其成为药物发现的非凡工具。本综述梳理了柔性酶技术的历史及其在非经典肽合成和筛选中的应用。
