Inhibitory effect of CDK9 inhibitor FIT-039 on hepatitis B virus propagation
Inhibitory effect of CDK9 inhibitor FIT-039 on hepatitis B virus propagation
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DOI：
10.1016/j.antiviral.2016.08.008
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发表时间：
2016-09-01
影响因子：
7.6
通讯作者：
Moriishi, Kohji
中科院分区：
文献类型：
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作者：
Tanaka, Tomohisa;Okuyama-Dobashi, Kaori;Moriishi, Kohji
目前针对B型肝炎病毒（HBV）的治疗由于共价闭合环状DNA（cccDNA）等的稳定群体而不能完全消除HBV基因组，已知FIT-039是细胞周期蛋白依赖性激酶（CDK）9抑制剂，其抑制多种DNA病毒（包括HSV、HPV和人腺病毒）的复制。在这项研究中，我们研究了FIT-039对HBV感染的抗病毒作用。在FIT-039存在下用HBV感染表达人牛磺胆酸钠共转运多肽的HepG 2细胞（HepG 2/NTCP细胞）。FIT-039剂量依赖性地减少细胞内病毒RNA、核衣壳相关病毒DNA和上清液病毒抗原，而在感染细胞中没有细胞毒性（IC 50 = 0.33 μ M，CC 50> 50 μ M）。FIT-039的抗病毒活性在病毒感染的早期阶段是突出的，尽管该化合物不抑制preS 1与HepG 2/NTCP细胞的结合。FIT-039减少HBV复制或HBV感染细胞中的cccDNA。此外，恩替卡韦的抗病毒活性通过与FIT-039组合在具有感染HBV的人肝细胞的嵌合小鼠中显著增强。所有小鼠均未出现显著的药物相关体重或血清人血白蛋白浓度变化。这些数据表明，CDK 9抑制剂FIT-039是一种有希望的抗HBV感染的候选药物。(C)2016爱思唯尔B. V.保留所有权利。
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 mu M, CC50 > 50 mu M). 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. (C) 2016 Elsevier B.V. All rights reserved.