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Selective Small Molecule Recognition of RNA Base Pairs
ACS Combinatorial Science Pub Date : 2018-07-02 00:00:00 , DOI: 10.1021/acscombsci.8b00049
Hafeez S Haniff 1 , Amanda Graves 1 , Matthew D Disney 1
Affiliation  

Many types of RNAs exist in the human transcriptome, yet only the bacterial ribosome has been exploited as a small molecule drug target. Aside from rRNA, other cellular RNAs such as noncoding RNAs have primarily secondary structure and limited tertiary structure. Within these secondary structures of noncanonically paired and unpaired regions, more than 50% are base paired, with most efforts to target these structures focused on looped regions. A void exists in the availability of small molecules capable of targeting RNA base pairs. Using chemoinformatics, an RNA-focused library enriched for nitrogen-containing heterocycles was developed and tested for binding RNA base pairs, leading to the identification of six selective and previously unknown binders. While all binders were derivatives of benzimidazoles, those with expanded aromatic polycycles bound selectively to AU pairs, while those with flexible urea side chains bound selectively to GC pairs. Two of the three selective GC pair binders can distinguish between two different orientations, 5′GG/3′CC and 5′GC/3′CG pairs. Furthermore, all six molecules showed >50-fold selectivity for RNA over DNA. These studies provide foundational knowledge to better exploit RNA as targets for small molecule chemical probes or lead therapeutics by using modules that target RNA base pairs.

中文翻译:


RNA 碱基对的选择性小分子识别



人类转录组中存在多种类型的 RNA,但只有细菌核糖体被用作小分子药物靶点。除 rRNA 外,其他细胞 RNA(例如非编码 RNA)主要具有二级结构和有限的三级结构。在这些非规范配对和未配对区域的二级结构中,超过 50% 是碱基配对的,而针对这些结构的大多数努力都集中在环状区域。能够靶向 RNA 碱基对的小分子的可用性存在空白。利用化学信息学,开发了一个富含含氮杂环的以 RNA 为中心的文库,并测试了其与 RNA 碱基对的结合,从而鉴定了六种选择性且以前未知的结合物。虽然所有粘合剂都是苯并咪唑衍生物,但具有扩展芳族多环的粘合剂选择性地结合到AU对,而具有柔性脲侧链的粘合剂选择性地结合到GC对。三种选择性 GC 对结合剂中的两种可以区分两种不同的方向:5'GG/3'CC 和 5'GC/3'CG 对。此外,所有六种分子对 RNA 的选择性均是 DNA 的 3E50 倍。这些研究提供了基础知识,以便更好地利用 RNA 作为小分子化学探针的靶标,或通过使用针对 RNA 碱基对的模块来引导治疗。
更新日期:2018-07-02
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