Riboswitches: discovery of drugs that target bacterial gene-regulatory RNAs.
Riboswitches: discovery of drugs that target bacterial gene-regulatory RNAs.
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DOI：
10.1021/ar200039b
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发表时间：
2011-12-20
影响因子：
18.3
通讯作者：
Ferre-D'Amare, Adrian R.
中科院分区：
文献类型：
--
作者：
Deigan, Katherine E.;Ferre-D'Amare, Adrian R.
核糖开关是在21世纪世纪的最初几年发现的，是对多种代谢物和第二信使的细胞内浓度做出响应的基因调节mRNA结构域。它们控制着许多致病菌的必需基因，是抗生素和化学生物学工具开发的一类新的生物分子靶标。已知核糖开关有五种基因调控机制。大多数细菌核糖开关响应于配体结合而调节转录终止或翻译起始。所有已知的真核核糖开关和一些细菌核糖开关的例子都是通过选择性剪接来控制基因表达的。glmS核糖开关广泛存在于革兰氏阳性菌中，是通过配体结合激活的催化RNA。它的自我切割使它所属的mRNA不稳定。最后，已知反式作用核糖开关的一个实例。三维（3D）结构已被确定的13个结构不同的核糖开关类的代表，提供原子水平的洞察其配体识别的机制。虽然细胞和病毒RNA通常作为潜在的药物靶标引起了人们的兴趣，但核糖开关由于其配体结合口袋中展示的小分子识别策略的多样性和复杂性而显示出特殊的前景。此外，在已知的结构化RNA结构域中，核糖开关进化为识别小分子配体。核糖开关研究的结构和生物化学进展为发现新型核糖开关激活剂和抑制剂的方法的发展提供了动力。最近的理性药物设计工作集中在选择核糖开关类产生了少量的候选抗生素化合物，包括一个活跃在金黄色葡萄球菌感染的小鼠模型。目前正在开发适合核糖开关特异性药物发现的高通量方法。一种基于片段的筛选方法，采用平衡透析，可能是普遍有用的，已经取得了早期的成功。核糖开关介导的基因调控被细菌广泛采用，然而，只有硫胺素焦磷酸响应核糖开关迄今已被发现在真核生物。因此，核糖开关作为抗菌药物的靶标特别有吸引力。事实上，已经发现具有先前未知机制的抗菌剂通过结合核糖开关并导致异常基因表达而发挥作用。
Riboswitches, which were discovered in the first years of the XXI century, are gene-regulatory mRNA domains that respond to the intracellular concentration of a variety of metabolites and second messengers. They control essential genes in many pathogenic bacteria, and represent a new class of biomolecular target for the development of antibiotics and chemical-biological tools. Five mechanisms of gene regulation are known for riboswitches. Most bacterial riboswitches modulate transcription termination or translation initiation in response to ligand binding. All known examples of eukaryotic riboswitches and some bacterial riboswitches control gene expression by alternative splicing. The glmS riboswitch, widespread in Gram-positive bacteria, is a catalytic RNA activated by ligand binding. Its self-cleavage destabilizes the mRNA of which it is part. Finally, one example of trans-acting riboswitch is known. Three-dimensional (3D) structures have been determined of representatives of thirteen structurally distinct riboswitch classes, providing atomic-level insight into their mechanisms of ligand recognition. While cellular and viral RNAs in general have attracted interest as potential drug targets, riboswitches show special promise due to the diversity and sophistication of small molecule recognition strategies on display in their ligand binding pockets. Moreover, uniquely among known structured RNA domains, riboswitches evolved to recognize small molecule ligands. Structural and biochemical advances in the study of riboswitches provide an impetus for the development of methods for the discovery of novel riboswitch activators and inhibitors. Recent rational drug design efforts focused on select riboswitch classes have yielded a small number of candidate antibiotic compounds, including one active in a mouse model of Staphylococcus aureus infection. The development of high-throughput methods suitable for riboswitch-specific drug discovery is ongoing. A fragment-based screening approach employing equilibrium dialysis that may be generically useful has had early success. Riboswitch-mediated gene regulation is widely employed by bacteria; however, only the thiamine pyrophosphate-responsive riboswitch has thus far been found in eukaryotes. Thus, riboswitches are particularly attractive as targets for antibacterials. Indeed, antimicrobials with previously unknown mechanisms have been found to function by binding riboswitches and leading to aberrant gene expression.
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