Over the past 20 years, the field of RNA-targeted therapeutics has advanced based on discoveries of modified oligonucleotide chemistries, and an ever-increasing understanding of how to apply cellular assays to identify oligonucleotides with improved pharmacological properties in vivo. Locked nucleic acid (LNA), which exhibits high binding affinity and potency, is widely used for this purpose. Our understanding of RNA biology has also expanded tremendously, resulting in new approaches to engage RNA as a therapeutic target. Recent observations indicate that each oligonucleotide is a unique entity, and small structural differences between oligonucleotides can often lead to substantial differences in their pharmacological properties. Here, we outline new principles for drug discovery exploiting oligonucleotide diversity to identify rare molecules with unique pharmacological properties.

在过去的20年中，基于修饰的寡核苷酸化学的发现以及对如何应用细胞分析法来鉴定具有改善的体内药理学特性的寡核苷酸的认识不断增强，靶向RNA的治疗药物的领域不断发展。。具有高结合亲和力和效力的锁定核酸（LNA）被广泛用于此目的。我们对RNA生物学的理解也得到了极大的扩展，从而产生了将RNA用作治疗靶标的新方法。最近的观察表明，每种寡核苷酸都是独特的实体，并且寡核苷酸之间的小结构差异通常会导致其药理特性发生实质性差异。在这里，我们概述了利用寡核苷酸多样性来发现具有独特药理特性的稀有分子的药物发现新原理。