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

• DOI: 10.1371/journal.pone.0197664
• Publication Date: 2018-05-21T18:32:53Z
• Authors: Yuta Tsukamoto; Sotaro Ikeda; Koji Uwai; Riho Taguchi; Kazuaki Chayama; Takemasa Sakaguchi; Ryo Narita; Wan-Ling Yao; Fumihiko Takeuchi; Yukie Otakaki; Koichi Watashi; Takaji Wakita; Hiroki Kato; Takashi Fujita
• Keywords: Rosmarinic acid

Current therapeutics for hepatitis B virus (HBV) patients such as nucleoside analogs (NAs) are effective; however, new antiviral drugs against HBV still desired. Since the interaction between epsilon (ε) sequence of pregenomic RNA and viral polymerase (Pol) is a key step in replication cycle, we aimed to identify small compounds its inhibition, established pull-down assay system detection ε-RNA-binding-Pol. Screening showed that 5 out 3,965 inhibited ε-Pol binding, identified rosmarinic acid, which exhibited specificity, potential agent. In order examine anti-HBV effects HBV-infected primary human hepatocytes from humanized mouse liver were treated with acid. The acid treatment decreased components including amounts extracellular DNA negligible cytotoxicity. We also investigated combined NA, lamivudine. slightly enhanced activity lamivudine, suggesting targeted by distinct NA. analyzed an additional 25 derivatives, found ε-Pol. Structural comparisons these derivatives implied "two phenolic hydroxyl groups at both ends" "caffeic acid-like structure" critical inhibition binding. Collectively, our results demonstrate inhibits cells specifically targeting