Rosmarinic acid is a novel inhibitor for Hepatitis B virus replication targeting viral epsilon RNA-polymerase interaction

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Rosmarinic acid is a novel inhibitor for Hepatitis B virus replication targeting viral epsilon RNA-polymerase interaction. / 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.

In: PLOS ONE, Vol. 13, No. 5, e0197664, 21.05.2018.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Tsukamoto, Y, Ikeda, S, Uwai, K, Taguchi, R, Chayama, K, Sakaguchi, T, Narita, R, Yao, WL, Takeuchi, F, Otakaki, Y, Watashi, K, Wakita, T, Kato, H & Fujita, T 2018, 'Rosmarinic acid is a novel inhibitor for Hepatitis B virus replication targeting viral epsilon RNA-polymerase interaction', PLOS ONE, vol. 13, no. 5, e0197664. https://doi.org/10.1371/journal.pone.0197664

APA

Tsukamoto, Y., Ikeda, S., Uwai, K., Taguchi, R., Chayama, K., Sakaguchi, T., ... Fujita, T. (2018). Rosmarinic acid is a novel inhibitor for Hepatitis B virus replication targeting viral epsilon RNA-polymerase interaction. PLOS ONE, 13(5), [e0197664]. https://doi.org/10.1371/journal.pone.0197664

CBE

Tsukamoto Y, Ikeda S, Uwai K, Taguchi R, Chayama K, Sakaguchi T, Narita R, Yao WL, Takeuchi F, Otakaki Y, Watashi K, Wakita T, Kato H, Fujita T. 2018. Rosmarinic acid is a novel inhibitor for Hepatitis B virus replication targeting viral epsilon RNA-polymerase interaction. PLOS ONE. 13(5). https://doi.org/10.1371/journal.pone.0197664

MLA

Vancouver

Tsukamoto Y, Ikeda S, Uwai K, Taguchi R, Chayama K, Sakaguchi T et al. Rosmarinic acid is a novel inhibitor for Hepatitis B virus replication targeting viral epsilon RNA-polymerase interaction. PLOS ONE. 2018 May 21;13(5). e0197664. https://doi.org/10.1371/journal.pone.0197664

Author

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. / Rosmarinic acid is a novel inhibitor for Hepatitis B virus replication targeting viral epsilon RNA-polymerase interaction. In: PLOS ONE. 2018 ; Vol. 13, No. 5.

Bibtex

@article{a161b54e3f1b447cbb7ccfe1ff1c6c52,
title = "Rosmarinic acid is a novel inhibitor for Hepatitis B virus replication targeting viral epsilon RNA-polymerase interaction",
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.",
author = "Yuta Tsukamoto and Sotaro Ikeda and Koji Uwai and Riho Taguchi and Kazuaki Chayama and Takemasa Sakaguchi and Ryo Narita and Yao, {Wan Ling} and Fumihiko Takeuchi and Yukie Otakaki and Koichi Watashi and Takaji Wakita and Hiroki Kato and Takashi Fujita",
year = "2018",
month = "5",
day = "21",
doi = "10.1371/journal.pone.0197664",
language = "English",
volume = "13",
journal = "P L o S One",
issn = "1932-6203",
publisher = "public library of science",
number = "5",

}

RIS

TY - JOUR

T1 - Rosmarinic acid is a novel inhibitor for Hepatitis B virus replication targeting viral epsilon RNA-polymerase interaction

AU - Tsukamoto, Yuta

AU - Ikeda, Sotaro

AU - Uwai, Koji

AU - Taguchi, Riho

AU - Chayama, Kazuaki

AU - Sakaguchi, Takemasa

AU - Narita, Ryo

AU - Yao, Wan Ling

AU - Takeuchi, Fumihiko

AU - Otakaki, Yukie

AU - Watashi, Koichi

AU - Wakita, Takaji

AU - Kato, Hiroki

AU - Fujita, Takashi

PY - 2018/5/21

Y1 - 2018/5/21

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85047391181&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0197664

DO - 10.1371/journal.pone.0197664

M3 - Journal article

C2 - 29782545

AN - SCOPUS:85047391181

VL - 13

JO - P L o S One

JF - P L o S One

SN - 1932-6203

IS - 5

M1 - e0197664

ER -