Screening for inhibitor of episomal DNA identified dicumarol as a hepatitis B virus inhibitor.

Autor: Fumihiko Takeuchi, Sotaro Ikeda, Yuta Tsukamoto, Yoshikazu Iwasawa, Chen Qihao, Yukie Otakaki, Ouda Ryota, Wan-Ling Yao, Ryo Narita, Hijikata Makoto, Koichi Watashi, Takaji Wakita, Koh Takeuchi, Kazuaki Chayama, Amane Kogure, Hiroki Kato, Takashi Fujita
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: PLoS ONE, Vol 14, Iss 2, p e0212233 (2019)
Druh dokumentu: article
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0212233
Popis: Currently, there is no available therapy to eradicate hepatitis B virus (HBV) in chronically infected individuals. This is due to the difficulty in eliminating viral covalently closed circular (ccc) DNA, which is central to the gene expression and replication of HBV. We developed an assay system for nuclear circular DNA using an integration-deficient lentiviral vector. This vector produced non-integrated circular DNA in nuclei of infected cells. We engineered this vector to encode firefly luciferase to monitor the lentiviral episome DNA. We screened 3,840 chemicals by this assay for luciferase-reducing activity and identified dicumarol, which is known to have anticoagulation activity. We confirmed that dicumarol reduced lentiviral episome DNA. Furthermore, dicumarol inhibited HBV replication in cell culture using NTCP-expressing HepG2 and primary human hepatocytes. Dicumarol reduced intracellular HBV RNA, DNA, supernatant HBV antigens and DNA. We also found that dicumarol reduced the cccDNA level in HBV infected cells, but did not affect HBV adsorption/entry. This is a novel assay system for screening inhibitors targeting nuclear cccDNA and is useful for finding new antiviral substances for HBV.
Databáze: Directory of Open Access Journals
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