RNA interference with 2',4'-bridged nucleic acid analogues.
In this study, a number of 2',4'-BNA- and 2',4'-BNA(NC)-modified siRNAs were designed and synthesized. Their thermal stability, nuclease resistance and gene silencing properties against cultured mammalian cells were evaluated and compared with those of natural siRNAs. The 2',4'-BNA- and 2',4'-BNA(NC)-modified siRNAs (named siBNA and siBNA(NC), respectively) showed very high T(m) values, were remarkably stable in serum sample and showed promising RNAi properties equal to those exhibited by natural siRNAs. Thermally stable siBNAs composed of slightly modified sense and antisense strands were capable of suppressing gene expression equal to that of natural siRNA. A number of modifications on the sense strand by 2',4'-BNA or 2',4'-BNA(NC), either consecutively or separated by natural RNA nucleotides, is tolerable in RNAi machinery. Modifications at the Argonauate (Ago2) cleavage site of the sense strand (9-11th positions from the 5'-end of the sense strand) produced variable results depending on siRNA composition. Mostly, modification at the 10th position diminished siRNA activity. In moderately modified siRNAs, modification at the 11th position displayed usual RNAi activity, while modification at the 9th position showed variable results depending on siRNA composition.
Abdur Rahman
S M
SM
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
Sato
Hiroyuki
H
Tsuda
Naoto
N
Haitani
Sunao
S
Narukawa
Keisuke
K
Imanishi
Takeshi
T
Obika
Satoshi
S
D001952:Bridged-Ring Compounds / Q000737:chemistry*; D002460:Cell Line; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D009690:Nucleic Acid Conformation; D009711:Nucleotides / Q000737:chemistry*; D012313:RNA / Q000737:chemistry*; D034622:RNA Interference / Q000502:physiology*; D034741:RNA, Small Interfering / Q000737:chemistry*
C527205:2',4'-BNA(NC); D001952:Bridged-Ring Compounds; D009711:Nucleotides; D034741:RNA, Small Interfering; D012313:RNA