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使用家用化学,动态和静态控制反感性寡核酸的非目标相互作用

Chisato Terada^1,2, Kaho Oh¹, Ryutaro Tsubaki¹

¹Department of Chemistry of Biofunctional Molecules, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

Nature communications

|December 2, 2023

概括

研究人员开发了一种名为BROTHERS (BRace On a THERapeutic aSo) 的新型纳米架构,通过将反意义寡核酸 (ASO) 与核酸 (PNA) 链结合起来. 这种创新的ASO/PNA混合物通过减少非目标相互作用和毒性,显著提高药物安全性.

科学领域:

橄核酸的治疗药物
药物输送系统是药物输送系统.
分子相互作用分子相互作用.

背景情况:

反感性寡核酸 (ASO) 具有治疗潜力,但由于非目标相互作用和相关的临床安全责任而面临挑战.
当前的ASO修改虽然已经很先进,但并不能完全消除意外生物相互作用的风险.

研究的目的:

开发一种新的纳米架构,BROTHERS (BRace On a THERapeutic aSo),以减轻非目标相互作用,并提高ASO药物的安全性.
研究ASO/核酸 (PNA) 混合物的潜力,以提高治疗安全性和疗效.

主要方法:

一个纳米架构 (BROTHERS) 的设计和合成,包括一个标准的gapmer ASO和一个部分互补的PNA链.
描述ASO/PNA杂交特性,包括非特异性蛋白质结合和热力学稳定性.
对向RNA相互作用和肝毒性和向敲击活动的评估进行体内位介导的链位移 (TMSD) 的评估.

主要成果:

与标准ASO相比,开发的ASO/PNA杂交物 (BROTHERS) 显示其非特异性蛋白结合能力降低.
优化的BROTHERS在体内促进了TMSD,有效地减少了与RNA的非目标杂交.
优化的BROTHERS在体内显著减轻了肝毒性,同时保持了母ASO的目标击倒效率.

结论:

BROTHERS纳米架构代表了一种新的治疗药物类别,对ASO的输送和安全性有潜在的变革性影响,特别是在肝外应用中.
这种方法提供了一个有希望的策略来减少ASO相关的毒性,并可能有助于阐明ASO毒性机制.

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