title: Control of HCV Replication With iMIRs, a Novel Anti-RNAi Agent.
abstract: MicroRNAs (miRNAs) serve important roles in regulating various physiological activities through RNA interference (RNAi). miR-122 is an important mediator of RNAi that is known to control hepatitis C virus (HCV) replication and is being investigated in clinical trials as a target for anti-HCV therapy. In this study, we developed novel oligonucleotides containing non-nucleotide residues, termed iMIRs, and tested their abilities to inhibit miR-122 function. We compared the inhibitory effects of iMIRs and locked nucleic acids (LNAs) on HCV replication in OR6 cells, which contained full-length HCV (genotype 1b) and a luciferase reporter gene. We found that RNA-type iMIRs with bulge-type, imperfect complementarity with respect to miR-122 were 10-fold more effective than LNAs in inhibiting HCV replication and functioned in a dose-dependent manner. Moreover, iMIR treatment of OR6 cells reduced HCV replication without inducing interferon responses or cellular toxicity. Based on these results, we suggest that iMIRs can inhibit HCV replication more effectively than LNAs and are therefore promising as novel antiviral agents.
authors.affiliation: Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Itami
authors.affiliation: Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Eguchi
authors.affiliation: BONAC Corporation, Kurume, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Mizutani
authors.affiliation: BONAC Corporation, Kurume, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Aoki
authors.affiliation: BONAC Corporation, Kurume, Japan.
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Ohgi
authors.affiliation: Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kuroda
authors.affiliation: National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
authors.affiliation: Department of Tumor Virology, Okayama University, Okayama, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kato
authors.affiliation: Sharp Laboratory Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Hiroshi I
authors.initials: HI
authors.lastname: Suzuki
authors.affiliation: Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Kawada
authors.affiliation: Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan. Electronic address: 2079633@med.osaka-cu.ac.jp.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Murakami
keywords: RNA interference; anti-sense oligonucleotide; hepatitis C virus; interferon; locked nucleic acid; miRNA