State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Org Biomol Chem. 2012 Oct 7;10(37):7566-77. doi: 10.1039/c2ob26219c.
Antisense oligonucleotides and siRNAs are potential therapeutic agents and their chemical modifications play an important role to improve the properties and activities of oligonucleotides. Isonucleoside is a type of nucleoside analogue, in which the nucleobase is moved from C-1 to other positions of ribose. In this report, a novel isonucleoside 5 containing a 5'-CH(2)-extended chain at the sugar moiety was synthesized, thus isoadenosine 5a and isothymidine 5b were incorporated into a DNA single strand and siRNA. It was found that isonucleoside 5 modified oligonucleotides can form stable double helical structures with their complementary DNA and RNA and the stability towards nuclease and ability to activate RNase H are more promising compared with the unmodified, natural analogues. In siRNA, passenger strand modified with isonucleoside (5a/b) at 3' or 5' terminal can retain the silencing activity and minimize the passenger strand specific off-target effect.
反义寡核苷酸和 siRNA 是潜在的治疗药物，其化学修饰对于改善寡核苷酸的性质和活性起着重要作用。异核苷是一种核苷类似物，其中碱基从 C-1 移动到核糖的其他位置。在本报告中，合成了一种新型糖基部分含有 5'-CH(2)-扩展链的 5 位异核苷 5，从而将异腺苷 5a 和异胸腺嘧啶 5b 掺入 DNA 单链和 siRNA 中。结果发现，与未修饰的天然类似物相比，异核苷修饰的寡核苷酸可以与互补的 DNA 和 RNA 形成稳定的双螺旋结构，并且对核酸酶的稳定性和激活 RNase H 的能力更有前途。在 siRNA 中，在 3'或 5'末端用异核苷（5a/b）修饰的过客链可以保留沉默活性并最小化过客链的非特异性脱靶效应。
