Selective small-molecule inhibition of an RNA structural element
Selective small-molecule inhibition of an RNA structural element
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DOI：
10.1038/nature15542
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发表时间：
2015-10-29
期刊：
影响因子：
64.8
通讯作者：
Roemer, Terry
中科院分区：
文献类型：
--
作者：
Howe, John A.;Wang, Hao;Roemer, Terry
核糖开关是位于信使RNA中的非编码RNA结构，其结合内源性配体，例如特定代谢物或离子，以调节基因表达。因此，核糖开关作为一种新的，但在很大程度上未开发的新兴药物靶点。然而，证明这种潜力已被证明是困难的，并且仅限于结构相似的抗代谢物及其同源配体的半合成类似物，从而极大地限制了此类抑制剂所寻求的化学空间和选择性。在这里，我们报告的发现和表征的核糖核酸，细菌核黄素核糖开关，这是确定在一个表型筛选和作为一个结构不同的天然配体，黄素monlobenzide的合成模拟物，抑制核糖开关介导的ribB基因表达和抑制细菌细胞生长的高度选择性的化学调节剂。我们的研究结果表明，非编码RNA结构元件可能比以前预期的更广泛地被合成小分子靶向。
Riboswitches are non-coding RNA structures located in messenger RNAs that bind endogenous ligands, such as a specific metabolite or ion, to regulate gene expression. As such, riboswitches serve as a novel, yet largely unexploited, class of emerging drug targets. Demonstrating this potential, however, has proven difficult and is restricted to structurally similar antimetabolites and semi-synthetic analogues of their cognate ligand, thus greatly restricting the chemical space and selectivity sought for such inhibitors. Here we report the discovery and characterization of ribocil, a highly selective chemical modulator of bacterial riboflavin riboswitches, which was identified in a phenotypic screen and acts as a structurally distinct synthetic mimic of the natural ligand, flavin mononucleotide, to repress riboswitch-mediated ribB gene expression and inhibit bacterial cell growth. Our findings indicate that non-coding RNA structural elements may be more broadly targeted by synthetic small molecules than previously expected.