Inhibition of hepatitis B virus replication by targeting ribonucleotide reductase M2 protein

被引：42

作者：

Liu, Xia ^{[1
,5
]}

Xu, Zhijian ^{[2
]}

Hou, Chuanwei ^{[2
]}

Wang, Meng ^{[2
]}

Chen, Xinhuan ^{[1
,3
]}

Lin, Qinghui ^{[1
]}

Song, Rui ^{[1
]}

Lou, Meng ^{[1
]}

Zhu, Lijun ^{[1
]}

Qiu, Yunqing ^{[4
]}

Chen, Zhi ^{[4
]}

Yang, Chunhao ^{[2
]}

Zhu, Weiliang ^{[2
]}

Shao, Jimin ^{[1
]}

机构：

[1] Zhejiang Univ, Sch Med, Dept Pathol & Pathophysiol, Key Lab Dis Prote Zhejiang Prov,Res Ctr Air Pollu, Hangzhou 310058, Zhejiang, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China

[3] Zhengzhou Univ, Sch Med, Dept Pathol & Pathophysiol, Zhengzhou 450001, Peoples R China

[4] Zhejiang Univ, Coll Med, Affiliated Hosp 1, State Key Lab Infect Dis Diag & Treatment, Hangzhou 310003, Zhejiang, Peoples R China

[5] Zhejiang Chinese Med Univ, Clin Med Coll 2, Cent Lab, Hangzhou, Peoples R China

来源：

BIOCHEMICAL PHARMACOLOGY | 2016年 / 103卷

基金：

中国国家自然科学基金; 国家高技术研究发展计划(863计划);

关键词：

Hepatitis B virus; Viral genomic DNA and cccDNA synthesis; Human ribonucleotide reductase small subunit M2 (RRM2); Small molecule compounds; Drug synergism and drug resistance; HYDROXYUREA; COMBINATION; SUBUNIT; LIVER; HEPATOCYTES; NUCLEOSIDE; EXPRESSION; ANALOGS; CANCER;

D O I：

10.1016/j.bcp.2016.01.003

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Chronic hepatitis B virus (HBV) infection is a key factor for hepatocellular carcinoma worldwide. Ribonucleotide reductase (RR) regulates the deoxyribonucleoside triphosphates biosynthesis and serves as a target for anti-cancer therapy. Here, we demonstrate that RR is essential for HBV replication and the viral covalently-closed-circular DNA (cccDNA) synthesis in host liver cells. By performing computer-assisted virtual screening against the crystal structure of RR small subunit M2 (RRM2), osalmid, was identified as a potential RRM2-targeting compound. Osalmid was shown to be 10-fold more active in inhibiting RR activity than hydroxyurea, and significantly inhibited HBV DNA and cccDNA synthesis in HepG2.2.15 cells. In contrast, hydroxyurea and the RR large subunit (RRM1)-inhibitory drug gemcitabine showed little selective activity against HBV replication. In addition, osalmid also was shown to possess potent activity against a 3TC-resistant HBV strain, suggesting utility in treating drug-resistant HBV infections. Interestingly, osalmid showed synergistic effects with lamivudine (3TC) in vitro and, in vivo without significant toxicity, and was shown to inhibit RR activity in vivo, thus verifying its in vivo function. Furthermore, 4-cyclopropy1-2-fluoro-N-(4-hydroxyphenyl) benzamide (YZ51), a novel derivative of osalmid, showed higher efficacy than osalmid with more potent RR inhibitory activity. These results suggest that RRM2 might be targeted for HBV inhibition, and the RRM2-targeting compound osalmid and its derivative YZ51 could be a novel class of anti-HBV candidates with potential use for hepatitis B and HBV-related HCC treatment. (C) 2016 Elsevier Inc. All rights reserved.

引用

页码：118 / 128

页数：11

共 46 条

[1] Targeting the Achilles heel of the hepatitis B virus: a review of current treatments against covalently closed circular DNA [J].