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Issue 24, 2017
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Isonucleotide incorporation into middle and terminal siRNA duplexes exhibits high gene silencing efficacy and nuclease resistance

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Abstract

In this study, we introduced a pair of nucleotide enantiomers, D-/L-isonucleotides (D-/L-isoNA), to examine the interactions between siRNAs and their related proteins. The serum stability and gene-silencing activity of the modified siRNAs were systematically evaluated. Gene-silencing activity had a site-specific effect, and the incorporation of a single D-isoNA at the 8th position (counting from the 5′-terminus) in the antisense strand improved the gene-silencing activity by improving RISC loading and affecting the movement of the PIWI domain. D-isoNA incorporated at the terminus of siRNA including the 2nd position in the antisense strand and 3′-overhangs in the sense strand, especially the latter, enhanced nuclease resistance and prolonged the silencing retention time. In addition, L-isoNA incorporation into the middle of the sense strand enhanced activity. These results provide a chemical strategy for the modulation of siRNA gene-silencing activity and nuclease resistance.

Graphical abstract: Isonucleotide incorporation into middle and terminal siRNA duplexes exhibits high gene silencing efficacy and nuclease resistance

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Publication details

The article was received on 02 May 2017, accepted on 25 May 2017 and first published on 25 May 2017


Article type: Paper
DOI: 10.1039/C7OB01065F
Citation: Org. Biomol. Chem., 2017,15, 5161-5170
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    Isonucleotide incorporation into middle and terminal siRNA duplexes exhibits high gene silencing efficacy and nuclease resistance

    Y. Ma, S. Liu, Y. Wang, Y. Zhao, Y. Huang, L. Zhong, Z. Guan, L. Zhang and Z. Yang, Org. Biomol. Chem., 2017, 15, 5161
    DOI: 10.1039/C7OB01065F

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