Synthesis and biological evaluation of peptide-siRNA conjugates with phosphodiester unit as linker  

作　　者：WANG XiaoFeng HUANG Ye LIU Yang CHEN Yue JIN HongWei ZHENG Yi DU Quan YANG ZhenJun ZHANG LiHe 

机构地区：[1]The State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University [2]CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co.,Ltd.

出　　处：《Science China Chemistry》2013年第11期1542-1549,共8页中国科学（化学英文版）

基　　金：supported by the National Natural Science Foundation of China(20932001);the Ministry of Science and Technology of China(2012AA022501);the National Key Basic Research Program of China(2012CB720604)

摘　　要：In this paper,a series of peptide-siRNA conjugates with phosphodiester unit as the linker targeting to Cdc2 gene were synthesized by solid phase stepwise strategy.The conjugation of peptides at either 3’-terminus of siCdc2 bring no change to the classical A-form of RNA duplex,but slightly compromise the thermodynamic stability.Peptide conjugation at the 3’-terminus of sense strand could improve the serum stability obviously,however,the opposite peptide conjugation at the 3’-terminus of antisense strand shows no such influence.According to the results of artificial silencing activity assay system,peptide conjugation at 3’-terminus of antisense strand slightly weakens the silencing activity of siCdc2.But sense strand peptide conjugation exhibits similar silencing activity as native siCdc2,meanwhile,it could mitigate the unwanted off-target effect of sense strand targeting to its own mRNA.In this paper, a series of peptide-siRNA conjugates with phosphodiester unit as the linker targeting to Cdc2 gene were synthe- sized by solid phase stepwise strategy. The conjugation of peptides at either 3＇-terminus of siCdc2 bring no change to the classical A-form of RNA duplex, but slightly compromise the thermodynamic stability. Peptide conjugation at the 3＇-terminus of sense strand could improve the serum stability obviously, however, the opposite peptide conjugation at the 3＇-terminus of an- tisense strand shows no such influence. According to the results of artificial silencing activity assay system, peptide conjuga- tion at 3＇-terminus of antisense strand slightly weakens the silencing activity of siCdc2. But sense strand peptide conjugation exhibits similar silencing activity as native siCdc2, meanwhile, it could mitigate the unwanted off-target effect of sense strand targeting to its own mRNA.

关 键 词：SIRNA PEPTIDE conjugate solid synthesis 

分 类 号：TQ460.1[化学工程—制药化工]