Childs-Disney Jessica L, Tran Tuan, Vummidi Balayeshwanth R, Velagapudi Sai Pradeep, Haniff Hafeez S, Matsumoto Yasumasa, Crynen Gogce, Southern Mark R, Biswas Avik, Wang Zi-Fu, Tellinghuisen Timothy L, Disney Matthew D
Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA.
Mitsubishi Tanabe Pharma Corporation, 3-2-10, Dosho-machi, Chuo-ku, Osaka 541-8505, Japan.
Chem. 2018 Oct 11;4(10):2384-2404. doi: 10.1016/j.chempr.2018.08.003. Epub 2018 Sep 13.
Many RNAs cause disease; however, RNA is rarely exploited as a small-molecule drug target. Our programmatic focus is to define privileged RNA motif small-molecule interactions to enable the rational design of compounds that modulate RNA biology starting from only sequence. We completed a massive, library-versus-library screen that probed over 50 million binding events between RNA motifs and small molecules. The resulting data provide a rich encyclopedia of small-molecule RNA recognition patterns, defining chemotypes and RNA motifs that confer selective, avid binding. The resulting interaction maps were mined against the entire viral genome of hepatitis C virus (HCV). A small molecule was identified that avidly bound RNA motifs present in the HCV 30 UTR and inhibited viral replication while having no effect on host cells. Collectively, this study represents the first whole-genome pattern recognition between small molecules and RNA folds.
许多RNA会引发疾病；然而，RNA很少被用作小分子药物靶点。我们的项目重点是定义有优势的RNA基序与小分子的相互作用，以便从仅有的序列出发合理设计调节RNA生物学的化合物。我们完成了一项大规模的文库对文库筛选，探测了RNA基序与小分子之间超过5000万个结合事件。所得数据提供了一个丰富的小分子RNA识别模式百科全书，定义了赋予选择性、高亲和力结合的化学类型和RNA基序。针对丙型肝炎病毒（HCV）的整个病毒基因组挖掘所得的相互作用图谱。鉴定出一种小分子，它能高亲和力地结合HCV 3′UTR中存在的RNA基序并抑制病毒复制，同时对宿主细胞没有影响。总体而言，这项研究代表了小分子与RNA折叠之间的首次全基因组模式识别。
