Synthesis and silencing properties of siRNAs possessing lipophilic groups at their 3′-termini

Short-interfering RNAs (siRNAs) conjugated with lipophilic groups at their 3'-termini were synthesized. The properties of the synthesized siRNAs were examined in detail, and it was found that at low concentrations, their silencing abilities were dependent on the positions of the modi. cations and the types of organic molecules attached. Although the modi. cation of siRNAs with palmitic acid or oleic acid at the 3'-end slightly reduced their silencing activities, siRNAs had enough abilities to induce RNAi at 10 nM concentrations. On the other hand, the modi. cation of siRNAs with cholesterol at the 3'-end of the passenger strand was tolerated; however, the modi. cation at the guide strand significantly reduces its silencing activity. The siRNAs modified with the lipophilic groups did not possess ability to penetrate the plasma membranes of HT-1080 cells without the transfection reagent. However, the results described in this report will aid in designing novel siRNAs with cell membrane-permeable molecules. (C) 2008 Elsevier Ltd. All rights reserved.