以蛋白质为向的小分子药物通过核糖酶招募重新编程
Peiyuan Zhang1, Xiaohui Liu1, Daniel Abegg1
1Department of Chemistry, Scripps Research, Jupiter, Florida 33458, United States.
Journal of the American Chemical Society
|August 13, 2021
概括
将多维替药物用于向前体microRNA-21 (miR-21前体) 显著提高了选择性. 在小鼠模型中减轻疾病.
科学领域:
- 生物化学
- 分子生物学
- 药物发现
背景情况:
- 针对新点,特别是RNA的现有药物的重新编程带来了重大选择性挑战.
- 像Dovitinib这样的受体氨酸激酶 (RTK) 抑制剂与蛋白质标相互作用,但它们的RNA结合程度较少.
研究的目的:
- 研究dovitinib与RNA结构的结合.
- 合理设计一种用于向RNA降解的仿真化合物.
- 增强前体微RNA-21 (pre- miR-21) 的选择性,并评估治疗潜力.
主要方法:
- 研究了RNA折叠和小分子药物之间的结合相互作用.
- 鉴定了多维替尼与前miR-21的结合.
- 通过使用Dovitinib作为与RNase L相关的RNA识别元素,设计出一种仿真化合物.
- 在细胞和小鼠模型中评估化合物的活性和选择性.
主要成果:
- 发现多维替尼可以结合miR-21.
- 这种化学化合物对预米R-21的选择性比标准RTK的选择性有2500倍的转变.
- 嵌合体有效诱导了前miR-21的催化降解.
- 在三阴性乳腺癌和阿尔波特综合征的小鼠模型中观察到治疗效果.
结论:
- 通过嵌合物化合物的向RNA降解可以实现高选择性,即使在不同的生物分子类型 (蛋白质与RNA) 中.
- 这种方法为开发针对特定RNA过度表达的疾病的新疗法提供了有希望的策略.
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