title: Inhibitory effect of CDK9 inhibitor FIT-039 on hepatitis B virus propagation.
abstract: Current therapies for hepatitis B virus (HBV) cannot completely eliminate the HBV genome because of the stable population of covalently closed circular DNA (cccDNA) and so on. FIT-039, which is a cyclin-dependent kinase (CDK) 9 inhibitor, is known to suppress the replication of several DNA viruses including HSV, HPV and human adenovirus. In this study, we investigated the antiviral effect of FIT-039 on HBV infection. HepG2 cells expressing human sodium taurocholate cotransporting polypeptide (HepG2/NTCP cells) were infected with HBV in the presence of FIT-039. FIT-039 dose-dependently reduced intracellular viral RNA, nucleocapsid-associated viral DNA, and supernatant viral antigens without cytotoxicity in the infected cells (IC50 = 0.33 μM, CC50 > 50 μM). The antiviral activity of FIT-039 was prominent at an early phase of viral infection, although the compound did not inhibit preS1-binding to HepG2/NTCP cells. FIT-039 reduced cccDNA in HBV-replicating or HBV-infected cells. Furthermore, the antiviral activity of entecavir was significantly enhanced by the combination with FIT-039 in the chimeric mice having human hepatocytes infected with HBV. None of the mice had significant drug-related body weight or serum human-albumin concentration changes. These data suggest that CDK9 inhibitor FIT-039 is a promising antiviral candidate for HBV infection.
authors: Department of Microbiology, Graduate School of Medical Science, University of Yamanashi, Yamanashi 409-3898, Japan.
authors: Tomohisa
authors: T
authors: Tanaka
authors: Department of Microbiology, Graduate School of Medical Science, University of Yamanashi, Yamanashi 409-3898, Japan.
authors: Kaori
authors: K
authors: Okuyama-Dobashi
authors: Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors: Shuko
authors: S
authors: Murakami
authors: Department of Microbiology, Graduate School of Medical Science, University of Yamanashi, Yamanashi 409-3898, Japan.
authors: Wenjia
authors: W
authors: Chen
authors: Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
authors: Toru
authors: T
authors: Okamoto
authors: Division of Virology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
authors: Keiji
authors: K
authors: Ueda
authors: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Takamitsu
authors: T
authors: Hosoya
authors: Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
authors: Yoshiharu
authors: Y
authors: Matsuura
authors: Department of Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, Kanagawa 236-0004, Japan.
authors: Akihide
authors: A
authors: Ryo
authors: Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors: Yasuhito
authors: Y
authors: Tanaka
authors: Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors: Masatoshi
authors: M
authors: Hagiwara
authors: Department of Microbiology, Graduate School of Medical Science, University of Yamanashi, Yamanashi 409-3898, Japan. Electronic address: kmoriishi@yamanashi.ac.jp.
authors: Kohji
authors: K
authors: Moriishi
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors; D004270:DNA, Circular; D004279:DNA, Viral; D004195:Disease Models, Animal; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000188:drug therapy / Q000821:virology*; D006515:Hepatitis B virus / Q000187:drug effects*; D006801:Humans; D051379:Mice; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D004270:DNA, Circular; D004279:DNA, Viral; C000595272:FIT-039; D011725:Pyridines; D042863:Cyclin-Dependent Kinase 9
keywords: Antiviral; CDK9 inhibitor; HBV; Hepatitis B; Replication; cccDNA