Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695, USA.
J Am Chem Soc. 2010 Jun 16;132(23):7976-81. doi: 10.1021/ja910275u.
MicroRNAs are a recently discovered new class of important endogenous regulators of gene function. Aberrant regulation of microRNAs has been linked to various human diseases, most importantly cancer. Small molecule intervention of microRNA misregulation has the potential to provide new therapeutic approaches to such diseases. Here, we report the first small molecule inhibitors and activators of the liver-specific microRNA miR-122. This microRNA is the most abundant microRNA in the liver and is involved in hepatocellular carcinoma development and hepatitis C virus (HCV) infection. Our small molecule inhibitors reduce viral replication in liver cells and represent a new approach to the treatment of HCV infections. Moreover, small molecule activation of miR-122 in liver cancer cells selectively induced apoptosis through caspase activation, thus having implications in cancer chemotherapy. In addition to providing a new approach for the development of therapeutics, small molecule modifiers of miR-122 function are unique tools for exploring miR-122 biogenesis.
microRNAs 是一类新发现的重要内源性基因功能调控因子。microRNAs 的异常调控与多种人类疾病有关，尤其是癌症。小分子干预 microRNA 的失调有可能为这些疾病提供新的治疗方法。在这里，我们报告了第一个针对肝脏特异性 microRNA miR-122 的小分子抑制剂和激活剂。这种 microRNA 是肝脏中含量最丰富的 microRNA，参与肝癌的发展和丙型肝炎病毒 (HCV) 感染。我们的小分子抑制剂可降低肝细胞中的病毒复制，为治疗 HCV 感染提供了一种新方法。此外，小分子激活 miR-122 在肝癌细胞中通过半胱天冬酶激活选择性诱导细胞凋亡，因此对癌症化疗具有重要意义。除了为治疗药物的开发提供了一种新方法外，miR-122 功能的小分子调节剂也是探索 miR-122 生物发生的独特工具。
