Function Control of Anti-microRNA Oligonucleotides Using Interstrand Cross-Linked Duplexes

MicroRNA (miRNA)-guided argonaute (Ago) controls gene expression upon binding to the 3′ UTR of mRNA. The miRNA function can be competitively inhibited by single-stranded anti-miRNA oligonucleotides (AMOs). In this study, we constructed a novel type of AMO flanked by interstrand cross-linked 2′-O-met...

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Bibliographic Details
Published in:Molecular therapy. Nucleic acids 2018-03, Vol.10, p.64-74
Main Authors: Mie, Yasuhiro, Hirano, Yu, Kowata, Keiko, Nakamura, Akiyoshi, Yasunaga, Mayu, Nakajima, Yoshihiro, Komatsu, Yasuo
Format: Article
Language:English
Subjects:
antisense
argonaute
Cell division
Conformation
cross-link
Deoxyribonucleic acid
DNA
duplex
Gene expression
microRNA
MicroRNAs
miRNA
Nuclease
Oligonucleotides
Structure-function relationships
Therapeutic applications
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Summary:MicroRNA (miRNA)-guided argonaute (Ago) controls gene expression upon binding to the 3′ UTR of mRNA. The miRNA function can be competitively inhibited by single-stranded anti-miRNA oligonucleotides (AMOs). In this study, we constructed a novel type of AMO flanked by interstrand cross-linked 2′-O-methylated RNA duplexes (CLs) that confer a stable helical conformation. Compared with other structured AMOs, AMO flanked by CLs at the 5′ and 3′ termini exhibited much higher inhibitory activity in cells. Anti-miRNA activity, nuclease resistance, and miRNA modification pattern distinctly differed according to the CL-connected positions in AMOs. Moreover, we found that the 3′-side CL improves nuclease resistance, whereas the 5′-side CL contributes to stable binding with miRNA in Ago upon interaction with the 3′ part of miRNA. These structure-function relationship analyses of AMOs provide important insights into the function control of Ago-miRNA complexes, which will be useful for basic miRNA research as well as for determining therapeutic applications of AMO. [Display omitted]
ISSN:2162-2531
2162-2531
DOI:10.1016/j.omtn.2017.11.003