MicroRNAs (miRNAs) are noncoding RNA molecules of 22–24 nucleotides that are estimated to regulate thousands of genes in humans, and their dysregulation has been implicated in many diseases. MicroRNA-122 (miR-122) is the most abundant miRNA in the liver and has been linked to the development of hepatocellular carcinoma and hepatitis C virus (HCV) infection. Its role in these diseases renders miR-122 a potential target for small-molecule therapeutics. Here, we report the discovery of a new sulfonamide class of small-molecule miR-122 inhibitors from a high-throughput screen using a luciferase-based reporter assay. Structure–activity relationship (SAR) studies and secondary assays led to the development of potent and selective miR-122 inhibitors. Preliminary mechanism-of-action studies suggest a role in the promoter-specific transcriptional inhibition of miR-122 expression through direct binding to the liver-enriched transcription factor hepatocyte nuclear factor 4α. Importantly, the developed inhibitors significantly reduce HCV replication in human liver cells.

中文翻译：

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小分子对 MicroRNA miR-122 的转录抑制可减少肝细胞中丙型肝炎病毒的复制

微小 RNA (miRNA) 是 22-24 个核苷酸的非编码 RNA 分子，据估计可调节人类数千个基因，它们的失调与许多疾病有关。MicroRNA-122 (miR-122) 是肝脏中最丰富的 miRNA，与肝细胞癌和丙型肝炎病毒 (HCV) 感染的发展有关。它在这些疾病中的作用使 miR-122 成为小分子治疗的潜在靶标。在这里，我们报告了使用基于荧光素酶的报告分析从高通量筛选中发现了一种新的磺胺类小分子 miR-122 抑制剂。构效关系 (SAR) 研究和二次分析导致了有效和选择性 miR-122 抑制剂的开发。初步作用机制研究表明，通过直接结合富含肝脏的转录因子肝细胞核因子 4α，在 miR-122 表达的启动子特异性转录抑制中发挥作用。重要的是，开发的抑制剂显着减少了人类肝细胞中的 HCV 复制。