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一个2'-O-Methoxyethyl Phosphorothioate拼接切换寡核酸合物的合物显示在内分泌体中被捕获的增加

Alyssa C Hill¹, J Philipp Becker¹, Daria Slominski¹

¹Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Eidgenössische Technische Hochschule Zürich (ETH Zürich), Zürich 8093, Switzerland.

|November 6, 2023

概括

反感性寡核酸 (ASOs) 需要改善细胞传递以增强基因表达调制. 将核定位信号 (NLS) 酸与拼接切换寡核酸 (SSO) 结合,改善了核积累,但需要转染或内分体破坏才能进行拼接切换活动.

科学领域:

分子生物学分子生物学
氧核酸治疗药物治疗药物
基因表达规范基因表达规范

背景情况:

反感性寡核酸 (ASOs) 受到细胞区间传输的限制.
拼接切换型寡核酸 (SSO) 显示出治疗潜力,但面临着交付挑战.

研究的目的:

为了增强SSO向细胞核的输送.
评估核定位信号 (NLS) 联对SSO活动的影响.
为了确定SSO结合效能的障碍.

主要方法:

通过 thiol-maleimide 化学合成 NLS-SSO 结合物.
通过CL-qPCR对SSO和结合细胞和亚细胞局部化的量化.
在体外对拼接切换活动的评估.
评估增强分娩的策略 (感染,黄素治疗).

主要成果:

一种NLS-SSO合物与母SSO相比,证明了核积累的改善.
在自由吸收时,NLS-SSO合物对拼接校正不活跃.
通过酸脂介导转染或洛昆治疗恢复了合切换活性.
认定了内分体捕获是对结合活性的主要障碍.

结论:

核定位信号的结合本身并不能保证SSO活动.
内体捕获显著阻碍了酸-寡核酸合物的治疗潜力.
有效的输送策略对于改性寡核酸的临床应用至关重要.

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