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工程Branaplam适应器利用自然Riboswitches的结构元素来利用结构元素.
Michael G Mohsen1,2, Matthew K Midy3, Aparaajita Balaji1
1Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06511, United States.
ACS chemical biology
|July 2, 2024
概括
研究人员开发了一种新型的RNA吸收酶来结合branaplam,这是以前针对神经系统疾病进行过的候选药物. 这种aptamer为复合物的重新用途提供了一个新的途径,利用其有利的安全性.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 候选药物在临床试验中失败的疗效可能具有宝贵的安全性和生物可用性.
- 药物重新定位需要特定的分子识别剂,如阿巴,来结合目标化合物.
- Branaplam是一种小分子,此前曾被用于脊柱肌肉缩和亨廷顿病.
研究的目的:
- 开发一种高亲和度RNA吸收酶,能够特异地结合候选药物branaplam.
- 通过创造一种新型的分子结合剂来探索重新利用branaplam的潜力.
主要方法:
- 在试验室选择 (SELEX) 在基于关氨酸-I рибо交换机阿普坦体支架的组合RNA池上进行.
- 使用理性设计和重新选择来优化选定aptamer候选者的结合亲和力.
- 对由此产生的aptamer变体进行了结构分析,将其与本地riboswitch支架进行了比较.
主要成果:
- 一个48核酸RNA的aptamer与一个解离常数 (Kd) 约150nM的branaplam成功开发.
- 优化aptamer保留了关键的结构元素 (伪节点,P2,P3),但缺少P1元素,这对自然的 рибо开关功能至关重要.
- 通过使用TPP带状交换机支架确定了替代的aptamer候选物,这表明了进一步开发的潜力.
结论:
- 一个特定的,高亲和度的RNA受体已经被设计为branaplam.
- 这种体为布兰帕姆的潜在药物重用提供了一个工具,利用其现有的安全数据.
- 这项研究证明了 рибо开关支架在小分子的aptamer开发中的多功能性.
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