Institut de Chimie de Nice UMR7272 CNRS, University of Nice , Parc Valrose, 06100 Nice, France.
ACS Chem Biol. 2014 Mar 21;9(3):711-21. doi: 10.1021/cb400668h. Epub 2014 Jan 3.
MicroRNAs (miRNAs) are a recently discovered category of small RNA molecules that regulate gene expression at the post-transcriptional level. Accumulating evidence indicates that miRNAs are aberrantly expressed in a variety of human cancers and revealed to be oncogenic and to play a pivotal role in initiation and progression of these pathologies. It is now clear that the inhibition of oncogenic miRNAs, defined as blocking their biosynthesis or their function, could find an application in the therapy of different types of cancer in which these miRNAs are implicated. Here we report the design, synthesis, and biological evaluation of new small-molecule RNA ligands targeting the production of oncogenic microRNAs. In this work we focused our attention on miR-372 and miR-373 that are implicated in the tumorigenesis of different types of cancer such as gastric cancer. These two oncogenic miRNAs are overexpressed in gastric cancer cells starting from their precursors pre-miR-372 and pre-miR-373, two stem-loop structured RNAs that lead to mature miRNAs after cleavage by the enzyme Dicer. The small molecules described herein consist of the conjugation of two RNA binding motives, i.e., the aminoglycoside neomycin and different natural and artificial nucleobases, in order to obtain RNA ligands with increased affinity and selectivity compared to that of parent compounds. After the synthesis of this new series of RNA ligands, we demonstrated that they are able to inhibit the production of the oncogenic miRNA-372 and -373 by binding their pre-miRNAs and inhibiting the processing by Dicer. Moreover, we proved that some of these compounds bear anti-proliferative activity toward gastric cancer cells and that this activity is likely linked to a decrease in the production of targeted miRNAs. To date, only few examples of small molecules targeting oncogenic miRNAs have been reported, and such inhibitors could be extremely useful for the development of new anticancer therapeutic strategies as well as useful biochemical tools for the study of miRNAs' pathways and mechanisms. Furthermore, this is the first time that a design based on current knowledge about RNA targeting is proposed in order to target miRNAs' production with small molecules.
微小 RNA（miRNAs）是一类新发现的小 RNA 分子，可在转录后水平调节基因表达。越来越多的证据表明，miRNAs 在多种人类癌症中异常表达，并被证实具有致癌作用，在这些疾病的发生和进展中发挥关键作用。现在很清楚，抑制致癌 miRNAs，即阻断其生物合成或功能，可以应用于涉及这些 miRNAs 的不同类型癌症的治疗。在这里，我们报告了针对致癌 microRNA 产生的新型小分子 RNA 配体的设计、合成和生物学评估。在这项工作中，我们将注意力集中在 miR-372 和 miR-373 上，它们与不同类型癌症（如胃癌）的肿瘤发生有关。这两种致癌 miRNAs 在胃癌细胞中从其前体 pre-miR-372 和 pre-miR-373 过度表达，这两种前体是经过酶 Dicer 切割后成熟 miRNAs 的茎环结构 RNA。本文所述的小分子由两个 RNA 结合基序的缀合组成，即氨基糖苷类抗生素新霉素和不同的天然和人工核苷，以获得与母体化合物相比具有更高亲和力和选择性的 RNA 配体。在合成了这一系列新的 RNA 配体后，我们证明它们能够通过结合其前体 miRNA 并抑制 Dicer 的加工来抑制致癌 miRNA-372 和 -373 的产生。此外，我们证明其中一些化合物对胃癌细胞具有抗增殖活性，并且这种活性可能与靶向 miRNA 产生的减少有关。迄今为止，只有少数针对致癌 miRNA 的小分子的例子被报道，并且这些抑制剂对于开发新的抗癌治疗策略以及作为 miRNA 途径和机制研究的有用生化工具可能非常有用。此外，这是第一次提出基于当前 RNA 靶向知识的设计，以便用小分子靶向 miRNA 的产生。
