Targeting RNA in mammalian systems with small molecules.
Targeting RNA in mammalian systems with small molecules.
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DOI：
10.1002/wrna.1477
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Hargrove AE
中科院分区：
文献类型：
--
作者：
Donlic A;Hargrove AE
RNA功能的识别超越了典型的蛋白质合成，挑战了分子生物学的中心教条。事实上，现在已知RNA直接调节许多重要的细胞过程，包括转录、剪接、翻译和表观遗传修饰。疾病中这些过程的错误调控导致了RNA作为治疗靶点的欣赏。这种潜力最初是在细菌和病毒中发现的，但在人类基因组测序后发现的新RNA类别，激发了对其在哺乳动物中疾病相关功能的探索。随着稳定的结构形成作为哺乳动物RNA的标志而进化，利用小分子特异性地探测RNA结构域的功能及其相互作用的前景正在获得越来越多的认识。迄今为止，研究人员已经在神经系统疾病、癌症和其他疾病中发现了通过结合扩展重复序列、microrna、g -四重体结构和RNA剪接位点来调节表型的生物活性小分子。从这些成功中吸取的经验教训既需要进一步的研究，也鼓励对大量哺乳动物rna的探索，这些rna的确切作用机制仍有待阐明。努力理解小分子RNA识别的基本原理，结合方法学发展的进步，应该为靶向新兴RNA类别（如长链非编码RNA）铺平道路。总之，这些努力可以释放基于rna调控过程的小分子探测的全部潜力，并使我们能够发现新的生物学和未被探索的人类疾病治疗干预途径。小分子已经成功地用于研究几种哺乳动物疾病中的RNA元件。这些进展鼓励探索新发现的具有治疗潜力的RNA相互作用。
The recognition of RNA functions beyond canonical protein synthesis has challenged the central dogma of molecular biology. Indeed, RNA is now known to directly regulate many important cellular processes, including transcription, splicing, translation, and epigenetic modifications. The misregulation of these processes in disease has led to an appreciation of RNA as a therapeutic target. This potential was first recognized in bacteria and viruses, but discoveries of new RNA classes following the sequencing of the human genome have invigorated exploration of its disease-related functions in mammals. As stable structure formation is evolving as a hallmark of mammalian RNAs, the prospect of utilizing small molecules to specifically probe the function of RNA structural domains and their interactions is gaining increased recognition. To date, researchers have discovered bioactive small molecules that modulate phenotypes by binding to expanded repeats, microRNAs, G-quadruplex structures, and RNA splice sites in neurological disorders, cancers, and other diseases. The lessons learned from achieving these successes both call for additional studies and encourage exploration of the plethora of mammalian RNAs whose precise mechanisms of action remain to be elucidated. Efforts towards understanding fundamental principles of small molecule-RNA recognition combined with advances in methodology development should pave the way towards targeting emerging RNA classes such as long non-coding RNAs. Together, these endeavours can unlock the full potential of small molecule-based probing of RNA-regulated processes and enable us to discover new biology and underexplored avenues for therapeutic intervention in human disease. Small molecules have been successfully used to study several mammalian RNA elements in disease. These advances encourage exploration of newly discovered RNA interactions with therapeutic potential.
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