Synthesis and properties of novel L-isonucleoside modified oligonucleotides and siRNAs.
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.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Jun
J
Zhang
Yue
Y
Chen
Ye
Y
Huang
Hong-Wei
HW
Jin
Ren-Ping
RP
Qiao
Lei
L
Xing
Liang-Ren
LR
Zhang
Zhen-Jun
ZJ
Yang
Li-He
LH
Zhang
D020868:Gene Silencing / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D008156:Luciferases / Q000235:genetics; D015394:Molecular Structure; D009705:Nucleosides / Q000737:chemistry*; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013997:Time Factors
D009705:Nucleosides; D009841:Oligonucleotides; D034741:RNA, Small Interfering; D008156:Luciferases