Instituto de Química Física 'Rocasolano' , CSIC, Serrano 119, 28006 Madrid, Spain.
ACS Chem Biol. 2014 Jul 18;9(7):1559-66. doi: 10.1021/cb500100z. Epub 2014 May 28.
Telomeric repeat-containing RNA (TERRA) is a novel and very attractive antitumoral target. Here, we report the first successful application of (19)F-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 (19)F- and (1)H 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.
端粒重复 RNA（TERRA）是一种新颖且极具吸引力的抗肿瘤靶标。在这里，我们首次成功应用 19F-NMR 基于片段的筛选方法来鉴定与 RNA 分子（如 TERRA）结合的化学多样性化合物。我们构建了一个由 355 个氟化片段组成的文库，并检查了它们与长端粒 RNA 作为靶分子的相互作用。筛选结果鉴定出 20 个命中物（命中率为 5.6%）。对于一些结合物，通过 19F 和 1H NMR 以及 CD 熔融实验证实了它们与 TERRA 的相互作用。我们还探索了配体对 RNA G-四链体的选择性，并发现一些命中物不与其他核酸（如 tRNA 和双链 DNA）相互作用，最重要的是，它们有利于端粒 DNA G-四链体中的桨状平行构象。这表明对这种特殊的四链体拓扑结构具有选择性识别，并且不同的配体可能识别桨状平行 G-四链体中的特定位点。这些特征使得一些所得的结合物成为基于片段的药物发现有前途的先导化合物。
