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タイトル: | A small molecule iCDM-34 identified by in silico screening suppresses HBV DNA through activation of aryl hydrocarbon receptor |
著者: | Furutani, Yutaka Hirano, Yoshinori Toguchi, Mariko Higuchi, Shoko Qin, Xian-Yang Yanaka, Kaori Sato-Shiozaki, Yumi Takahashi, Nobuaki Sakai, Marina Kongpracha, Pornparn Suzuki, Takehiro Dohmae, Naoshi Kukimoto-Niino, Mutsuko Shirouzu, Mikako Nagamori, Shushi Suzuki, Harukazu Kobayashi, Kaoru Masaki, Takahiro Koyama, Hiroo Sekiba, Kazuma Otsuka, Motoyuki Koike, Kazuhiko Kohara, Michinori Kojima, Soichi Kakeya, Hideaki https://orcid.org/0000-0002-4293-7331 (unconfirmed) Matsuura, Tomokazu |
著者名の別形: | 古谷, 裕 平野, 秀典 戸口, 真理子 樋口, 祥子 秦, 咸陽 屋中, 香織 佐藤(汐﨑), 裕美 髙橋, 伸明 酒井, 麻利奈 鈴木, 健裕 堂前, 直 柊元(新野), 睦子 白水, 美香子 永森, 收志 鈴木, 治和 小林, カオル 政木, 隆博 小山, 裕雄 關場, 一磨 大塚, 基之 小池, 和彦 小原, 道法 小嶋, 聡一 掛谷, 秀昭 松浦, 知和 |
キーワード: | Screening Small molecules Target identification |
発行日: | 22-Dec-2023 |
出版者: | Springer Nature |
誌名: | Cell Death Discovery |
巻: | 9 |
論文番号: | 216 |
抄録: | IFN-alpha have been reported to suppress hepatitis B virus (HBV) cccDNA via APOBEC3 cytidine deaminase activity through interferon signaling. To develop a novel anti-HBV drug for a functional cure, we performed in silico screening of the binding compounds fitting the steric structure of the IFN-alpha-binding pocket in IFNAR2. We identified 37 compounds and named them in silico cccDNA modulator (iCDM)-1–37. We found that iCDM-34, a new small molecule with a pyrazole moiety, showed anti-HCV and anti-HBV activities. We measured the anti-HBV activity of iCDM-34 dependent on or independent of entecavir (ETV). iCDM-34 suppressed HBV DNA, pgRNA, HBsAg, and HBeAg, and also clearly exhibited additive inhibitory effects on the suppression of HBV DNA with ETV. We confirmed metabolic stability of iCDM-34 was stable in human liver microsomal fraction. Furthermore, anti-HBV activity in human hepatocyte-chimeric mice revealed that iCDM-34 was not effective as a single reagent, but when combined with ETV, it suppressed HBV DNA compared to ETV alone. Phosphoproteome and Western blotting analysis showed that iCDM-34 did not activate IFN-signaling. The transcriptome analysis of interferon-stimulated genes revealed no increase in expression, whereas downstream factors of aryl hydrocarbon receptor (AhR) showed increased levels of the expression. CDK1/2 and phospho-SAMHD1 levels decreased under iCDM-34 treatment. In addition, AhR knockdown inhibited anti-HCV activity of iCDM-34 in HCV replicon cells. These results suggest that iCDM-34 decreases the phosphorylation of SAMHD1 through CDK1/2, and suppresses HCV replicon RNA, HBV DNA, and pgRNA formation. |
記述: | B型肝炎の完治が見込まれる新たな抗ウイルス薬の候補を発見 --新規の化合物iCDM-34がウイルスゲノムの合成を抑制--. 京都大学プレスリリース. 2023-12-22. |
著作権等: | © The Author(s) 2023 This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. |
URI: | http://hdl.handle.net/2433/286483 |
DOI(出版社版): | 10.1038/s41420-023-01755-w |
PubMed ID: | 38135680 |
関連リンク: | https://www.kyoto-u.ac.jp/ja/research-news/2023-12-22-0 |
出現コレクション: | 学術雑誌掲載論文等 |
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