用破坏RNA结构和X失活的化合物向Xist
Rodrigo Aguilar1,2,3, Kerrie B Spencer4, Barry Kesner1,2
1Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
Nature
|March 31, 2022
概括
研究人员开发了一种选方法,以寻找针对非编码RNA (ncRNA) 的小分子. 他们发现了一种结合Xist ncRNA的化合物, 破坏其功能并抑制细胞生长, 开辟了药物开发的新途径.
科学领域:
- 基因组学
- 分子生物学
- 药物发现
背景情况:
- 大多数人类基因组是非编码RNA (ncRNA),但药物主要向蛋白质.
- 由于ncRNA的形状灵活性和结构复杂性,对其进行向是具有挑战性的.
- 越来越多的疾病与ncRNA有关,这凸显了对ncRNA向药物的需求.
研究的目的:
- 为识别结合ncRNA的小分子制定选策略.
- 识别和描述针对Xist ncRNA的小分子.
- 研究Xist ncRNA向的功能后果.
主要方法:
- 开发了一种选策略来识别结合ncRNA的小分子.
- 用于体外和体内测试来测试化合物与Xist ncRNA的结合.
- 使用小角度X射线散射来分析RNA结构.
- 评估化合物结合对蛋白相互作用,表观遗传修饰和细胞过程的影响.
主要成果:
- 鉴定了一种类似药物的小分子 (X1),该分子特别结合Xist ncRNA的RepA基因.
- X1结合会降低RepA的形状灵活性.
- X1可以取代PRC2和SPEN蛋白,抑制H3K27的三甲基化,并抑制X染色体的失活.
- X1 呈现出女性特有的细胞分化和生长抑制.
结论:
- 药物类化合物可以系统地向ncRNA.
- 小分子可以破坏RNA结构和表观遗传功能.
- 这种方法扩大了针对ncRNA相关疾病的药物开发空间.
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