Targeting RNA using small molecules is now established as a very promising strategy for many therapeutic applications since coding and non‐coding RNAs bear a pivotal role both in viral and bacterial infections as well as in human pathologies such as cancer. Here, we focused on the targeting of HIV‐1 TAR RNA as a promising target for the development of new anti‐HIV therapies but also as an ideal model to validate the discovery of original RNA ligands. First, we performed an initial screening of a library of compounds against TAR that led to the discovery of verapamil, a marketed calcium‐channel blocker, as a promising chemical structure for the development of new RNA ligands. The synthesis of a series of analogs of verapamil led to promising structure activity relationships and to the discovery of compound 2h, a conjugate between verapamil and indole fragment, as an efficient and selective TAR binder able to inhibit Tat/TAR interaction with an IC50 of 18.8 µM. This work supports the potential of library screening for the discovery of original and selective RNA ligands and illustrates how existing drugs directed against protein targets still need to be studied for RNA binding as a promising strategy in the field of RNA targeting by small molecules.

中文翻译：

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揭示维拉帕米的RNA结合特性并制备新衍生物作为HIV-1 Tat-TAR相互作用的抑制剂

由于编码和非编码RNA在病毒和细菌感染以及人类病理疾病（例如癌症）中都起着关键作用，因此现在已经确立了使用小分子靶向RNA的许多治疗应用前景非常广阔的策略。在这里，我们专注于将HIV-1 TAR RNA作为开发新的抗HIV疗法的有希望的目标，同时也是验证原始RNA配体发现的理想模型。首先，我们对抗TAR的化合物库进行了初步筛选，从而发现了市售的钙通道阻滞剂维拉帕米，作为开发新RNA配体的有前途的化学结构。一系列维拉帕米类似物的合成导致了有希望的结构活性关系，并导致了化合物2h的发现，维拉帕米与吲哚片段之间的结合物，作为一种有效且选择性的TAR结合物，能够抑制Tat / TAR相互作用，IC50为18.8 µM。这项工作为发现原始和选择性的RNA配体提供了库筛选的潜力，并说明了如何仍需要研究针对蛋白质靶标的现有药物进行RNA结合，这是小分子靶向RNA领域中的一种有前途的策略。