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Title: Rosmarinic acid is a novel inhibitor for Hepatitis B virus replication targeting viral epsilon RNA-polymerase interaction
Authors: Tsukamoto, Yuta
Ikeda, Sotaro
Uwai, Koji
Taguchi, Riho
Chayama, Kazuaki
Sakaguchi, Takemasa
Narita, Ryo
Yao, Wan-Ling
Takeuchi, Fumihiko
Otakaki, Yukie
Watashi, Koichi
Wakita, Takaji
Kato, Hiroki
Fujita, Takashi
Author's alias: 塚本, 雄太
池田, 宗太郎
上井, 幸司
田口, 莉帆
茶山, 一彰
坂口, 剛正
成田, 亮
竹内, 文彦
大高木, 結媛
渡士, 幸一
脇田, 隆字
加藤, 博己
藤田, 尚志
Issue Date: 21-May-2018
Publisher: Public Library of Science (PLoS)
Journal title: PLOS ONE
Volume: 13
Issue: 5
Thesis number: e0197664
Abstract: Current therapeutics for hepatitis B virus (HBV) patients such as nucleoside analogs (NAs) are effective; however, new antiviral drugs against HBV are still desired. Since the interaction between the epsilon (ε) sequence of HBV pregenomic RNA and viral polymerase (Pol) is a key step in the HBV replication cycle, we aimed to identify small compounds for its inhibition, and established a pull-down assay system for the detection of ε-RNA-binding-Pol. Screening showed that 5 out of 3, 965 compounds inhibited ε-Pol binding, and we identified rosmarinic acid, which exhibited specificity, as a potential antiviral agent. In order to examine the anti-HBV effects of rosmarinic acid, HBV-infected primary human hepatocytes from a humanized mouse liver were treated with rosmarinic acid. The rosmarinic acid treatment decreased HBV components including the amounts of extracellular HBV DNA with negligible cytotoxicity. We also investigated the combined effects of rosmarinic acid and the NA, lamivudine. rosmarinic acid slightly enhanced the anti-HBV activity of lamivudine, suggesting that the HBV replication step targeted by rosmarinic acid is distinct from that of NA. We analyzed an additional 25 rosmarinic acid derivatives, and found that 5 also inhibited ε-Pol. Structural comparisons between these derivatives implied that the “two phenolic hydroxyl groups at both ends” and the “caffeic acid-like structure” of rosmarinic acid are critical for the inhibition of ε-Pol binding. Collectively, our results demonstrate that rosmarinic acid inhibits HBV replication in HBV-infected cells by specifically targeting ε-Pol binding.
Rights: © 2018 Tsukamoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI(Published Version): 10.1371/journal.pone.0197664
PubMed ID: 29782545
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