Herein, we have demonstrated that the siRNA activity could be enhanced by incorporating the guide strand in the RISC complex through thermodynamic asymmetry caused by mU-based destabilizing modifications. A nuclease stability study revealed that 2'-OMe-mU and 2'-OEt-mU modifications slightly improved the half-lives of siRNA strands in human serum. In the gene silencing assay, 2'-OMe-mU modification at the 3'-overhang and cleavage site of the passenger strand in anti-renilla and anti-Bcl-2 siRNA duplexes were well-tolerated and exhibited improved gene silencing activity. However, gene silencing activity was attenuated when these modifications were incorporated at position 3 in the seed region of the antisense strand. The molecular modeling studies using these modifications at the seed region with the MID domain of hAGO2 explained that the 2'-alkoxy group makes steric interactions with the amino acid residues of the hAGO2 protein.
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| http://dx.doi.org/10.1021/acsmedchemlett.4c00140 | DOI Listing |
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