A meditation on accelerating the development of small molecule medicines targeting RNA.
A meditation on accelerating the development of small molecule medicines targeting RNA.
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关于加速开发针对 RNA 的小分子药物的思考。
DOI：
10.1080/17460441.2022.2084528
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发表时间：
2023
影响因子：
6.3
通讯作者：
Disney,MatthewD
中科院分区：
文献类型：
--
作者：
Yang,Xueyi;Childs-Disney,JessicaL;Disney,MatthewD
长期以来，RNA一直是小分子药物的靶标。20世纪40年代，韦克斯曼发现了天然产物链霉素，它取消了RNA介导的关键过程，即细菌蛋白质合成，提供了一种救命的抗菌剂[1]。目前核糖核酸的复兴很大程度上可以追溯到21世纪初人类基因组测序[2，3]。最引人注目的发现是，人类基因组的标准开放阅读框比预期的要少得多。此外，虽然人类基因组的大部分被转录成RNA(80%)，但较少的基因组被转录成蛋白质(2%)。有趣的是，RNA的生物学功能，无论是编码还是非编码，都是由它的结构决定的。因此，现在是部署针对致病RNA的小分子战略并提供精确药物的时候了。小分子与RNA靶标中的三维折叠相互作用，为基于寡核苷酸的模式提供了一种重要的替代方法。例如，可以对小分子进行药物优化，以提高组织的透过率，最大限度地减少靶外和最大限度地提高靶上事件。
RNA has long been a target for small-molecule medicines. In the 1940s, Waksman discovered the natural product Streptomycin, which abrogates a critical RNA-mediated process, ie, bacterial protein synthesis, providing a lifesaving antibacterial agent [1]. Much of the current renaissance in RNA can be traced to the sequencing of the human genome in the early 2000s [2, 3]. The most striking observation was that the human genome has many fewer canonical open reading frames than anticipated. Furthermore, while much of the human genome is transcribed into RNA (80%), a lesser amount is translated into protein (2%). Interestingly, the biological function of an RNA, whether coding and noncoding, is conferred by its structure. Thus, the time is right to deploy small-molecule strategies to target disease-causing RNAs and provide precision medicines. Small molecules interact with the three-dimensional folds in an RNA target and offer an important alternative to oligonucleotidebased modalities. For example, small molecules can be medicinally optimized for tissue penetrance and to minimize offtarget and maximize on-target events.