Development of antiviral LNA gapmers targeting functional stem-loop structures in tick-borne flavivirus genomes
- 1Department of Viral Ecology, National Research Center for the Control and Prevention of Infectious Diseases, Nagasaki University, Nagasaki 852-8523, Japan
- 2Nihon University Veterinary Research Center, Fujisawa, Kanagawa 252-0880, Japan; Laboratory of Biomedical Science, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa 252-0880, Japan
- 3Department of Viral Ecology, National Research Center for the Control and Prevention of Infectious Diseases, Nagasaki University, Nagasaki 852-8523, Japan; Corresponding author: Kentaro Yoshii, Department of Viral Ecology, National Research Center for the Control and Prevention of Infectious Diseases, Nagasaki University, Nagasaki 852-8523, Japan.
Abstract
Antisense oligonucleotide gapmers degrade target RNA in a sequence-specific and RNase H-dependent manner and are emerging as a promising antiviral strategy. Locked nucleic acid-modified gapmers have shown activity against several pathogenic viruses. Tick-borne encephalitis virus is widely distributed across Eurasia, with approximately 10,000 cases reported annually, and the absence of approved therapies represents a significant public health concern. In this study, we designed 71 locked nucleic acid-modified gapmers targeting structural elements within the untranslated regions of the single-stranded positive-sense RNA genome of tick-borne encephalitis virus. The antiviral efficacy of gapmers selected via in silico analysis was evaluated using a replicon system and infectious virus assays. Gapmers targeting stem-loop structures in the 3′ untranslated region effectively inhibited viral replication. Optimizing the length and composition of the lead gapmers further enhanced antiviral potency. Sequence alignment analysis revealed that the target regions of the optimized gapmers were highly conserved among the three major subtypes of tick-borne encephalitis virus. Accordingly, the optimized gapmers markedly inhibited replication of a highly pathogenic strain, suggesting broad-spectrum activity. Collectively, our findings support the development of locked nucleic acid-modified gapmers as therapeutics against tick-borne encephalitis virus and other tick-borne flaviviruses.
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BibTeX
@article{okamoto2026development,
title = {{Development of antiviral LNA gapmers targeting functional stem-loop structures in tick-borne flavivirus genomes}},
author = {Shunsuke Okamoto and Mizuki Fukuta and Yuji Fujii and Minato Hirano and Yusuke Echigoya and Kentaro Yoshii},
journal = {Molecular Therapy: Nucleic Acids},
year = {2026},
month = nov,
doi = {10.1016/j.omtn.2026.103144},
url = {https://doi.org/10.1016/j.omtn.2026.103144},
note = {CC BY},
}
RIS
TY - JOUR
TI - Development of antiviral LNA gapmers targeting functional stem-loop structures in tick-borne flavivirus genomes
AU - Shunsuke Okamoto
AU - Mizuki Fukuta
AU - Yuji Fujii
AU - Minato Hirano
AU - Yusuke Echigoya
AU - Kentaro Yoshii
PY - 2026
DA - 2026/11/06
JO - Molecular Therapy: Nucleic Acids
DO - 10.1016/j.omtn.2026.103144
UR - https://doi.org/10.1016/j.omtn.2026.103144
AB - Antisense oligonucleotide gapmers degrade target RNA in a sequence-specific and RNase H-dependent manner and are emerging as a promising antiviral strategy. Locked nucleic acid-modified gapmers have shown activity against several pathogenic viruses. Tick-borne encephalitis virus is widely distributed across Eurasia, with approximately 10,000 cases reported annually, and the absence of approved therapies represents a significant public health concern. In this study, we designed 71 locked nucleic acid-modified gapmers targeting structural elements within the untranslated regions of the single-stranded positive-sense RNA genome of tick-borne encephalitis virus. The antiviral efficacy of gapmers selected via in silico analysis was evaluated using a replicon system and infectious virus assays. Gapmers targeting stem-loop structures in the 3′ untranslated region effectively inhibited viral replication. Optimizing the length and composition of the lead gapmers further enhanced antiviral potency. Sequence alignment analysis revealed that the target regions of the optimized gapmers were highly conserved among the three major subtypes of tick-borne encephalitis virus. Accordingly, the optimized gapmers markedly inhibited replication of a highly pathogenic strain, suggesting broad-spectrum activity. Collectively, our findings support the development of locked nucleic acid-modified gapmers as therapeutics against tick-borne encephalitis virus and other tick-borne flaviviruses.
SN - 2162-2531
ER -