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

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...

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Bibliographic Details
Published in:Organic & biomolecular chemistry 2017-06, Vol.15 (24), p.5161-5170
Main Authors: Ma, Yuan, Liu, Shuang, Wang, Yusi, Zhao, Yuanhe, Huang, Ye, Zhong, Lijun, Guan, Zhu, Zhang, Lihe, Yang, Zhenjun
Format: Article
Language:English
Subjects:
Gene Silencing
Nucleic Acid Conformation
Nucleotides - genetics
Nucleotides - metabolism
Ribonucleases - metabolism
RNA, Small Interfering - genetics
RNA, Small Interfering - metabolism
Stereoisomerism
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Summary: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.
ISSN:1477-0520
1477-0539
DOI:10.1039/c7ob01065f