Inhibitory effect of CDK9 inhibitor FIT-039 on hepatitis B virus propagation
| Autor: | Yasuhito Tanaka, Takamitsu Hosoya, Shuko Murakami, Toru Okamoto, Keiji Ueda, Kaori Okuyama-Dobashi, Yoshiharu Matsuura, Akihide Ryo, Kohji Moriishi, Wenjia Chen, Tomohisa Tanaka, Masatoshi Hagiwara |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Hepatitis B virus Pyridines Population medicine.disease_cause Virus Replication Antiviral Agents Hepatitis B virus PRE beta Cell Line 03 medical and health sciences chemistry.chemical_compound Mice Cyclin-dependent kinase Virology medicine Animals Humans education Cytotoxicity Pharmacology education.field_of_study biology cccDNA Entecavir Hep G2 Cells Hepatitis B Molecular biology Cyclin-Dependent Kinase 9 digestive system diseases Disease Models Animal 030104 developmental biology chemistry DNA Viral biology.protein DNA Circular DNA medicine.drug |
| Zdroj: | Antiviral research. 133 |
| ISSN: | 1872-9096 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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