Structure–Activity Relationship of Flavin Analogues That Target the Flavin Mononucleotide Riboswitch,ACS Chemical Biology

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Structure–Activity Relationship of Flavin Analogues That Target the Flavin Mononucleotide Riboswitch
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-08-14 00:00:00 , DOI: 10.1021/acschembio.8b00533
Quentin Vicens ₁ , Estefanía Mondragón ₁ , Francis E. Reyes ₁ , Philip Coish ₂ , Paul Aristoff ₃ , Judd Berman ₄ , Harpreet Kaur ₄ , Kevin W. Kells ₄ , Phil Wickens ₄ , Jeffery Wilson ₄ , Robert C. Gadwood ₅ , Heinrich J. Schostarez ₅ , Robert K. Suto ₆ , Kenneth F. Blount ₂ , Robert T. Batey ₁

Affiliation

The flavin mononucleotide (FMN) riboswitch is an emerging target for the development of novel RNA-targeting antibiotics. We previously discovered an FMN derivative, 5FDQD, that protects mice against diarrhea-causing Clostridium difficile bacteria. Here, we present the structure-based drug design strategy that led to the discovery of this fluoro-phenyl derivative with antibacterial properties. This approach involved the following stages: (1) structural analysis of all available free and bound FMN riboswitch structures; (2) design, synthesis, and purification of derivatives; (3) in vitro testing for productive binding using two chemical probing methods; (4) in vitro transcription termination assays; and (5) resolution of the crystal structures of the FMN riboswitch in complex with the most mature candidates. In the process, we delineated principles for productive binding to this riboswitch, thereby demonstrating the effectiveness of a coordinated structure-guided approach to designing drugs against RNA.

中文翻译：

针对黄素单核苷酸核糖开关的黄素类似物的结构-活性关系

黄素单核苷酸（FMN）核糖开关是开发新型靶向RNA的抗生素的新兴目标。我们之前发现了一种FMN衍生物5FDQD，可以保护小鼠免于引起腹泻的艰难梭菌细菌。在这里，我们介绍了基于结构的药物设计策略，该策略导致了这种具有抗菌特性的氟代苯基衍生物的发现。该方法涉及以下阶段：（1）对所有可用的自由和结合的FMN核糖开关结构进行结构分析；（2）衍生物的设计，合成和纯化；（3）使用两种化学探测方法进行体外生产结合性测试；（4）体外转录终止测定；（5）具有最成熟候选物的FMN核糖开关的晶体结构的分辨率。在此过程中，我们描述了与该核糖开关有效结合的原理，从而证明了设计针对RNA的药物协同结构指导方法的有效性。

更新日期：2018-08-14

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