酸和2'-O-甲基改性单链寡核酸的序列和结构依赖性细胞毒性
Laura V Croft1, Mark Fisher1, Tabassum Khair Barbhuiya2
1School of Biomedical Sciences, Centre for Genomics and Personalised Health, Cancer and Ageing Research Program at Translational Research Institute, Faculty of Health, Queensland University of Technology, Brisbane, Australia.
Nucleic acid therapeutics
|April 22, 2024
概括
化学修饰增强了治疗性单链寡核酸 (SSO),但可能导致毒性. 修改后的SSO中稳定的发针结构与细胞毒性增加相关,指导更安全的治疗设计.
科学领域:
- 橄核酸的治疗药物
- 化学生物学是化学生物学.
- 药物发现 药物发现
背景情况:
- 单链寡核酸 (SSO) 是一个不断增长的治疗类,包括反意义寡核酸,microRNAs和aptamers.
- 化学修饰,如酸骨架和2'-O-甲基核糖,提高SSO的稳定性和药理动力学.
- 这些修改还可以通过非目标相互作用和细胞干扰诱导毒性.
研究的目的:
- 选一个改进的SSO图书馆,以检测细胞毒性.
- 调查修改后的SSO的结构-细胞毒性关系.
- 确定优化SSO治疗配置文件的设计考虑因素.
主要方法:
- 在两种癌细胞系中选了277个酸和2'-O-甲基修饰的SSO.
- 使用循环二元化,核磁共振和分子动力学模拟.
- 分析SSO结构,形状和基组成 (纯氨酸与pyrimidine).
主要成果:
- 形成稳定的发针结构的修改后的SSO比扩展形状的SSO更具有细胞毒性.
- 细胞毒性SSO与金胺相比,具有更高的平均纯素组成.
- 对于修改后的SSO,建立了一个结构-细胞毒性关系.
结论:
- 稳定的发针结构的形成是影响SSO细胞毒性的关键因素.
- 考虑到针头形成的SSO的设计可以导致改善治疗概况.
- 这项研究为开发更安全,更有效的基于SSO的治疗方法提供了见解.
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