Issue 24, 2017

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

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

Supplementary files

Article information

Article type
Paper
Submitted
02 May 2017
Accepted
25 May 2017
First published
25 May 2017

Org. Biomol. Chem., 2017,15, 5161-5170

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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