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

Molecular Therapy: Nucleic Acids

Yu Hirano¹  Yasuo Komatsu¹  Akiyoshi Nakamura¹  Yasuhiro Mie¹  Keiko Kowata¹  Mayu Yasunaga²  Yoshihiro Nakajima² 

[1] Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 2-17-2-1 Tsukisamu-Higashi, Toyohira-ku, Sapporo 062-8517, Japan;Health Research Institute, AIST, 2217-14 Hayashi-cho, Takamatsu, Kagawa 761-0395, Japan;

关键词: microRNA;    antisense;    cross-link;    duplex;    argonaute;   

DOI  :  10.1016/j.omtn.2017.11.003

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown