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

Yuan MA, Shuang Liu, Yusi Wang, Yuanhe Zhao, Ye Huang, Lijun Zhong, Zhu Guan, Lihe Zhang, Zhenjun Yang*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5161-5170
Number of pages10
JournalOrganic and Biomolecular Chemistry
Volume15
DOIs
Publication statusPublished - 28 Jun 2017

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