基核酸修饰对siRNA的基性依赖性强化和结构影响
Mark K Schlegel1, Donald J Foster1, Alexander V Kel'in1
1Alnylam Pharmaceuticals , 300 Third Street, Cambridge, Massachusetts 02142, United States.
Journal of the American Chemical Society
|June 2, 2017
概括
糖核酸 (GNA) 修改增强了小干扰RNA (siRNA) 的稳定性和功效. 加入 (S) - GNA 改善了体外和体内疗效,为治疗提供了有前途的发展.
科学领域:
- 生物化学
- 分子生物学
- 氧核酸化学
背景情况:
- 小干扰RNA (siRNA) 疗法受到核酶敏感性和传递挑战的限制.
- 乙烯基核酸类似物有可能改善寡核酸的稳定性和功能.
- 葡萄糖核酸 (GNA) 是一种 siRNA 修改物,用于增强治疗性质.
研究的目的:
- 研究将糖核酸 (GNA) 纳入siRNA复合体的结构和功能影响.
- 评估 (S) -和 (R) -GNA立体异构体对RNA复杂完整性和基配对的影响.
- 评估GNA修饰的siRNAs的核酶耐药性,体外功效和体内功效.
主要方法:
- 用GNA修饰的RNA复合体的晶体结构的确定.
- 热化分析以评估双重稳定性
- 试验室实力测试和蛇毒酶耐药性测试.
- 在小鼠体内进行皮下注射的研究,向的是transthyretin (TTR).
主要成果:
- (S) -GNA的结合对双重结构的影响最小,而 (R) -GNA则会破坏骨干和基础配对.
- 与 (R) - GNA变体相比, (S) - GNA修饰的siRNA在体外具有显著的强度.
- GNA修改增加了对蛇毒酶的抵抗力.
- 在小鼠中,GNA修改的siRNA保持了体内功效, (S) - GNA的效果提高了2倍.
- 用GNA-T观察到反向的沃森-克里克基对,用GNA-C和GNA-G提高稳定性.
结论:
- 葡萄糖核酸 (GNA) 是一种可行的修改剂,可增强siRNA的稳定性和治疗效果.
- 在siRNA修饰方面, (S) - GNA优于 (R) - GNA,提高了功效和核酶耐药性.
- 经GNA修改的siRNA在体外和体内表现有前途,支持其治疗潜力.
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