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摘要 : 本期封面所示为与一个细菌核糖开关的RNA适配体结合在一起的小分子Ribocil的共晶结构。

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本期封面所示为与一个细菌核糖开关的RNA适配体结合在一起的小分子Ribocil的共晶结构。背景图像突显了该核糖开关适配体在Ribocil结合时所观察到的“蝴蝶折”构形。人们都知道迫切需要新型抗生素。现在,默克公司的Terry Roemer及同事描述了针对一个细菌核糖开关的一种新型合成抗生素。核糖开关是非编码RNA片段,其结构受某一个配体的影响,该配体通常是与被含核糖开关的基因编码的蛋白的功能相关的一个配体。这种新药(即Ribocil)阻断核黄素生物合成所需的ribB基因由“黄素单核苷酸核糖开关”介导的表达。Ribocil 抑制细菌细胞生长,在一个小鼠模型中能有效治疗细菌感染。封面图片: Sharon M. O’Brien


Selective small-molecule inhibition of an RNA structural element


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.

来源: Nature 浏览次数:0


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