小柯机器人

美国哈佛医学院Jeannie T. Lee研究团队提出，以破坏RNA结构和X失活的化合物靶向Xist。相关论文于2022年3月30日发表在《自然》杂志上。

他们设计了一种筛选策略并鉴定了结合非编码RNA原型Xist 的小分子。X1化合物具有药物样特性，可在体外和体内特异性结合Xist的RepA基序 。小角X射线散射分析表明 RepA可以采用多种构象，但在溶液中倾向于一种结构。X1结合减少了RepA的构象空间，取代了同源相互作用的蛋白质因子（PRC2 和 SPEN），抑制了组蛋白H3K27三甲基化，并阻止了X染色体失活的起始。X1以雌性特异性方式抑制细胞分化和生长。因此，RNA可以被破坏RNA结构和表观遗传功能的药物样化合物系统地靶向。

研究人员表示，尽管超过 98% 的人类基因组是非编码的，但市场上几乎所有的药物都针对约700 种疾病相关蛋白中的一种。历史上不愿投资于非编码RNA的部分原因是对药物靶标采用单一稳定构象的要求。大多数RNA可以采用几种具有相似稳定性的构象。RNA结构的确定也仍然具有挑战性。尽管如此，越来越多的疾病现在被归因于非编码RNA，而靶向它们的能力将极大地扩展药物开发的化学空间。

附：英文原文

Title: Targeting Xist with compounds that disrupt RNA structure and X inactivation

Author: Aguilar, Rodrigo, Spencer, Kerrie B., Kesner, Barry, Rizvi, Noreen F., Badmalia, Maulik D., Mrozowich, Tyler, Mortison, Jonathan D., Rivera, Carlos, Smith, Graham F., Burchard, Julja, Dandliker, Peter J., Patel, Trushar R., Nickbarg, Elliott B., Lee, Jeannie T.

Issue&Volume: 2022-03-30

Abstract: Although more than 98% of the human genome is non-coding1, nearly all of the drugs on the market target one of about 700 disease-related proteins. The historical reluctance to invest in non-coding RNA stems partly from requirements for drug targets to adopt a single stable conformation2. Most RNAs can adopt several conformations of similar stabilities. RNA structures also remain challenging to determine3. Nonetheless, an increasing number of diseases are now being attributed to non-coding RNA4 and the ability to target them would vastly expand the chemical space for drug development. Here we devise a screening strategy and identify small molecules that bind the non-coding RNA prototype Xist5. The X1 compound has drug-like properties and binds specifically the RepA motif6 of Xist in vitro and in vivo. Small-angle X-ray scattering analysis reveals that RepA can adopt multiple conformations but favours one structure in solution. X1 binding reduces the conformational space of RepA, displaces cognate interacting protein factors (PRC2 and SPEN), suppresses histone H3K27 trimethylation, and blocks initiation of X-chromosome inactivation. X1 inhibits cell differentiation and growth in a female-specific manner. Thus, RNA can be systematically targeted by drug-like compounds that disrupt RNA structure and epigenetic function. A molecule identified in a screen for compounds that bind the non-coding mouse RNA Xist blocks Xist-dependent X-chromosome inactivation, demonstrating the utility of this approach for identifying drugs that target RNA.

DOI: 10.1038/s41586-022-04537-z

Source: https://www.nature.com/articles/s41586-022-04537-z

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