Advancing small ligands targeting RNA for better binding affinity and specificity: A study of structural influence through molecular design approach
Advancing small ligands targeting RNA for better binding affinity and specificity: A study of structural influence through molecular design approach
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推进靶向 RNA 的小配体以获得更好的结合亲和力和特异性：通过分子设计方法研究结构影响
DOI：
10.1016/j.snb.2018.02.004
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发表时间：
2018-06-01
影响因子：
8.4
通讯作者：
Chow, Cheuk-Fai
中科院分区：
文献类型：
--
作者：
Wang, Cong;Lu, Yu-Jing;Chow, Cheuk-Fai
合成了具有RNA特异性结合特性的细胞可渗透荧光有机小分子，研究结构对结合亲和力和特异性两个决定因素的影响。在基于小分子的系统结构变化的RNA特异性结合配体开发领域，类似的研究很少。新开发的结构简单的配体显示出更高的RNA结合亲和力（平衡结合常数：PI 1，K = 4.50 × 10（5）M（-1）; PI2，K = 4.48 × 10（5）M（-1）），比研究充分的RNA选择性染料E36的高（K = 0.89 × 10（5）M（-1））。此外，活细胞成像（人前列腺癌细胞）的体内研究表明，这些小分子在与核仁和细胞质区域的RNA结合时能够提供强相互作用信号。该分子对RNA的相互作用特异性远高于其他类型的核酸，这进一步得到了核糖核酸酶（RNase）消化试验的支持。本研究的实验结果不仅提供了重要线索的荧光信号，结合亲和力，和特异性的进展与小RNA特异性结合配体通过分子支架的结构优化，但也提供了补充信息，在寻找铅配体靶向RNA序列使用高通量化合物筛选技术和分子模拟研究。(C)2018爱思唯尔B. V.保留所有权利。
The cell permeable small fluorescent organic molecules possessing RNA-specific binding property were synthesized for the study of structural influence on two determining factors of binding affinity and specificity. Similar investigations are scarce in the field of RNA-specific binding ligand development based on a systematic structural change of small molecules. The newly developed and structurally simple ligands show much higher RNA-binding affinity (equilibrium binding constant: PI1, K = 4.50 x 10(5)M(-1); PI2, K = 4.48 x 10(5)M(-1)) than that of a well-studied RNA-selective dye E36 (K = 0.89 x 10(5)M(-1)) by the introduction of an aminoethylpiperidine group on the quinolinium scaffold. In addition, the in vivo study of live cell imaging (human prostate cancer cells) indicated that these small molecules are able to provide strong interaction signals when binding with RNA in the region of nucleolus and cytoplasm. The interaction specificity of the molecule towards RNA is found much higher than other types of nucleic acids, which was further supported by the digest tests with ribonuclease (RNase). The experimental results of the present study not only provide important cues on the fluorescent signaling, binding affinity, and specificity advancement with the small RNA-specific binding ligands through structurally refinement of molecular scaffolds, but also give complementary information in searching lead ligands for targeting RNA sequence using high-throughput compound screening techniques and molecular modeling studies. (C) 2018 Elsevier B.V. All rights reserved.