Discovery of Selective Ligands for Telomeric RNA G-quadruplexes (TERRA) through 19F-NMR Based Fragment Screening
Discovery of Selective Ligands for Telomeric RNA G-quadruplexes (TERRA) through 19F-NMR Based Fragment Screening
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DOI：
10.1021/cb500100z
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发表时间：
2014-07-01
影响因子：
4
通讯作者：
Gonzalez, Carlos
中科院分区：
文献类型：
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作者：
Garavis, Miguel;Lopez-Mendez, Blanca;Gonzalez, Carlos
含端粒重复序列的RNA（TERRA）是一种新的、非常有吸引力的抗肿瘤靶点。在这里，我们报告的第一个成功的应用F-19-NMR片段为基础的筛选，以确定化学上不同的化合物，结合到RNA分子，如TERRA。我们建立了一个包含355个氟化片段的文库，并检测了它们与作为靶分子的长端粒RNA的相互作用。筛选结果鉴定出20个命中（命中率为5.6%）。对于许多粘合剂，它们与TERRA的相互作用通过F-19-和H-1 NMR以及CD熔融实验得到证实。我们还探索了RNA G-四链体配体的选择性，发现一些命中不与其他核酸，如tRNA和双链体DNA相互作用，最重要的是，有利于螺旋桨样的平行构象端粒DNA G-四链体。这表明，这种特定的四链体拓扑结构的选择性识别，不同的配体可以识别螺旋桨样平行G-四链体的特定位点。这些特征使得一些所得的结合剂有希望用于基于片段的药物发现的先导化合物。
Telomeric repeat-containing RNA (TERRA) is a novel and very attractive antitumoral target. Here, we report the first successful application of F-19-NMR fragment-based screening to identify chemically diverse compounds that bind to an RNA molecule such as TERRA. We have built a library of 355 fluorinated fragments, and checked their interaction with a long telomeric RNA as a target molecule. The screening resulted in the identification of 20 hits (hit rate of 5.6%). For a number of binders, their interaction with TERRA was confirmed by F-19- and H-1 NMR as well as by CD melting experiments. We have also explored the selectivity of the ligands for RNA G-quadruplexes and found that some of the hits do not interact with other nucleic acids such as tRNA and duplex DNA and, most importantly, favor the propeller-like parallel conformation in telomeric DNA G-quadruplexes. This suggests a selective recognition of this particular quadruplex topology and that different ligands may recognize specific sites in propeller-like parallel G-quadruplexes. Such features make some of the resulting binders promising lead compounds for fragment based drug discovery.