Discovery of Small Molecule Ligands for MALAT1 by Tuning an RNA-Binding Scaffold
Discovery of Small Molecule Ligands for MALAT1 by Tuning an RNA-Binding Scaffold
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DOI：
10.1002/anie.201808823
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发表时间：
2018-10-01
影响因子：
16.6
通讯作者：
Hargrove, Amanda E.
中科院分区：
文献类型：
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作者：
Donlic, Anita;Morgan, Brittany S.;Hargrove, Amanda E.
对致癌长链非编码RNA转移相关肺腺癌转录本1 (MALAT1) 3端的结构研究证实了其独特的三螺旋结构。这种结构使转录物积累，并且在几种癌症中发现高水平的MALAT1。在此，我们基于rna结合支架二苯呋喃（DPF）合成了一个小分子文库，并对其进行了多种核酸构建的筛选，首次证明了MALAT1三螺旋结构可以选择性地靶向小分子。计算分析揭示了亚基定位和组成对DPF形状和分子内相互作用的影响趋势，而分子内相互作用通常与选择性和结合强度相关。因此，这项工作为MALAT1三螺旋结构的化学探针开发提供了设计策略，并表明对RNA集中文库的综合分析可以产生选择性RNA识别的见解。
Structural studies of the 3-end of the oncogenic long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) confirmed a unique triple-helix structure. This structure enables accumulation of the transcript, and high levels of MALAT1 are found in several cancers. Here, we synthesize a small molecule library based on an RNA-binding scaffold, diphenylfuran (DPF), screen it against a variety of nucleic acid constructs, and demonstrate for the first time that the MALAT1 triple helix can be selectively targeted with small molecules. Computational analysis revealed a trend between subunit positioning and composition on DPF shape and intramolecular interactions, which in turn generally correlated with selectivity and binding strengths. This work thus provides design strategies toward chemical probe development for the MALAT1 triple helix and suggests that comprehensive analyses of RNA-focused libraries can generate insights into selective RNA recognition.