〈論文・報告〉センス鎖によるオフターゲット効果を低減するsiRNA の化学修飾

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  • 〈PAPERS and REPORTS〉Chemical Modification of siRNA Eliminating Off-target Effect by the Sense Strand

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For clinical applications of small interfering RNA (siRNA), chemical structure of siRNA should be optimized to be taken up into cells effectively, be resistant against nuclease digestion, be loaded onto RNA induced silencing complex (RISC) rapidly and correctly, bind to the target sequence of mRNA specifically, suppress the genetic expression efficiently and minimize off-target effects. In the present study, we investigated RNA interference (RNAi) efficiencies of siRNAs bearing 5’-O-methylthymidine (X) and 5’-aminothymidine (Z) at 5’-end of the strands. The results showed that X and Z at the 5’-end of the antisense strand gave a serious damage to siRNA to show almost no or largely reduced silencing effect. The results can be interpreted that RISC was destabilized by steric or electrostatic repulsion between the methyl group of X or the ammonium group of Z and the cationic residues in MID domain pocket of hAgo2. These results strongly suggested that modification of 5’-end of the sense strand with X and Z will eliminate an off-target effect of the strand.

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