...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nucleic Acid Therapeutics >Mesyl Phosphoramidate Oligonucleotides as Potential Splice-Switching Agents: Impact of Backbone Structure on Activity and Intracellular Localization
【24h】

Mesyl Phosphoramidate Oligonucleotides as Potential Splice-Switching Agents: Impact of Backbone Structure on Activity and Intracellular Localization

机译：叶片磷酸寡核苷酸作为潜在的剪接切换剂：骨干结构对活性和细胞内定位的影响

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

A series of 2 '-deoxy and novel 2 '-O-methyl and 2 '-O-(2-methoxyethyl) (2 '-MOE) oligonucleotides with internucleotide methanesulfonyl (mesyl, mu) or 1-butanesulfonyl (busyl, beta) phosphoramidate groups has been synthesized for evaluation as potential splice-switching oligonucleotides. Evaluation of their splice-switching activity in spinal muscular atrophy patient-derived fibroblasts revealed no significant difference in splice-switching efficacy between 2 '-MOE mesyl oligonucleotide and the corresponding phosphorothioate (nusinersen). Yet, a survival study with model neonatal mice has shown the antisense 2 '-MOE mesyl oligonucleotide to be inferior to nusinersen at the highest dose of 40 mg/kg. A reason for their lower activity in vivo as ascertained by cellular uptake study by fluorescent confocal microscopy in HEK293 cell line could possibly be ascribed to compromised endosomal release and/or nuclear uptake of the 2 '-OMe or 2 '-MOE mu- and beta-oligonucleotides compared to their phosphorothioate analog.
机译：合成了一系列2'-脱氧和新的2'-O-甲基和2'-O-（2-甲氧基乙基）（2'-MOE）寡核苷酸，它们带有核苷酸间的甲基磺酰（甲磺酸基，mu）或1-丁烯磺酰（丁磺酸基，β）磷酰胺基，以作为潜在的剪接开关寡核苷酸。对脊髓性肌萎缩症患者来源的成纤维细胞的剪接转换活性进行评估后发现，2'-MOE甲磺酸寡核苷酸和相应的硫代磷酸（nusinersen）之间的剪接转换效率没有显著差异。然而，一项针对模型新生小鼠的存活研究表明，在最高剂量为40 mg/kg时，反义2'-MOE甲磺酸寡核苷酸不如nusinersen。通过荧光共聚焦显微镜对HEK293细胞系进行细胞摄取研究，确定其体内活性较低的一个原因可能是，与硫代磷酸类似物相比，2'-OMe或2'-MOE mu-和β寡核苷酸的内质体释放和/或核摄取受损。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号