Jayaraj Gopal Gunanathan, Nahar Smita, Maiti Souvik
Chemical & Systems Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India 110020.
Chem Commun (Camb). 2015 Jan 18;51(5):820-31. doi: 10.1039/c4cc04514a. Epub 2014 Oct 20.
MicroRNAs (miRNAs) are a class of genomically encoded small RNA molecules (∼22nts in length), which regulate gene expression post transcriptionally. The term microRNA or miRNA was coined in 2001, and research in the past decade has shed light on their widespread occurrence, evolutionary conservation and tissue specific functions. It is estimated that they modulate the gene expression of approximately 60% of the mammalian genes by regulating the levels of target mRNAs to which they can bind on the basis of sequence complementarities. miRNAs are produced in a well coordinated series of steps from being transcribed in the nucleus to exerting their function in the cytoplasm. miRNAs are now implicated in diverse biological phenomena ranging from development to stress response which makes miRNAs one of the central regulatory molecules which modulate information flow along the central dogma of gene expression. More importantly, like any regulatory molecule, deregulation of miRNAs is causally associated with several diseases (mainly cancer) and is directly involved in a variety of pathophysiologies owing to their aberrant expression. Thus, modulation of miRNA levels is of prime therapeutic importance. Conventional methods of miRNA knockdown using chemically modified antisense-oligonucleotides have been explored extensively but face the challenges of modes of delivery, biostability and biodistribution. This calls for the development of more alternative and non-conventional methods to target miRNA. Small molecules targeting RNA chemical and structural space provide one such timely opportunity. In this article we first provide a brief overview of miRNA biogenesis and its disease associations. We then summarize the major developments in conventional oligonucleotide based approaches to miRNA knockdown and its status. We then focus on the more non-conventional methods like oligonucleotide enzymes and small molecules and provide an outlook on the future of such methods.
微小RNA（miRNA）是一类由基因组编码的小RNA分子（长度约为22个核苷酸），它们在转录后调节基因表达。“微小RNA”或“miRNA”这一术语于2001年被创造出来，在过去十年的研究中，人们对它们的广泛存在、进化保守性和组织特异性功能有了更深入的了解。据估计，它们通过调节与其基于序列互补性结合的靶mRNA水平，调控约60%的哺乳动物基因的表达。miRNA从在细胞核中被转录开始，经过一系列协调良好的步骤，最终在细胞质中发挥功能。miRNA现在涉及从发育到应激反应等多种生物学现象，这使得miRNA成为调节基因表达中心法则信息流的核心调节分子之一。更重要的是，与任何调节分子一样，miRNA的失调与多种疾病（主要是癌症）存在因果关联，并且由于其异常表达直接参与各种病理生理过程。因此，调节miRNA水平具有重要的治疗意义。使用化学修饰的反义寡核苷酸进行miRNA敲低的传统方法已被广泛探索，但面临着递送方式、生物稳定性和生物分布等挑战。这就需要开发更多替代的、非传统的方法来靶向miRNA。靶向RNA化学和结构空间的小分子提供了这样一个及时的机会。在本文中，我们首先简要概述miRNA的生物合成及其与疾病的关联。然后总结基于传统寡核苷酸的miRNA敲低方法的主要进展及其现状。接着我们将重点关注更非传统的方法，如寡核苷酸酶和小分子，并展望这些方法的未来。
