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

doi:10.1016/j.bcp.2016.01.003

	Inhibition of hepatitis B virus replication by targeting ribonucleotide reductase M2 protein
	Liu, Xia2,5 ; Xu, Zhijian4 ; Hou, Chuanwei 4; Wang, Meng 4; Chen, Xinhuan 1,5; Lin, Qinghui 5; Song, Rui 5; Lou, Meng 5; Zhu, Lijun 5; Qiu, Yunqing 3
刊名	BIOCHEMICAL PHARMACOLOGY
	2016-03-01
卷号	103 页码:118-128
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
ISSN号	0006-2952
DOI	10.1016/j.bcp.2016.01.003
文献子类	Article
英文摘要	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.
资助项目	National Natural Science Foundation of China[81372138] ; National Natural Science Foundation of China[30873094] ; National Natural Science Foundation of China[81572384] ; National Natural Science Foundation of China[81090421] ; 863 National High Technology Research and Development Program of China[2012AA020206] ; SKLDR/SIMM[SIMM1403ZZ-01]
WOS关键词	HEPATOCELLULAR-CARCINOMA ; IN-VITRO ; HYDROXYUREA ; INFECTION ; HEPATOCYTES ; COMBINATION ; THERAPY ; SUBUNIT ; CANCER ; LIVER
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000372858600011
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276115]
专题	药物化学研究室药物发现与设计中心
通讯作者	Yang, Chunhao; Zhu, Weiliang; Shao, Jimin
作者单位	1.Zhengzhou Univ, Sch Med, Dept Pathol & Pathophysiol, Zhengzhou 450001, Peoples R China; 2.Zhejiang Chinese Med Univ, Clin Med Coll 2, Cent Lab, Hangzhou, Peoples R China 3.Zhejiang Univ, Coll Med, Affiliated Hosp 1, State Key Lab Infect Dis Diag & Treatment, Hangzhou 310003, Zhejiang, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 5.Zhejiang Univ, Sch Med, Dept Pathol & Pathophysiol, Key Lab Dis Prote Zhejiang Prov,Res Ctr Air Pollu, Hangzhou 310058, Zhejiang, Peoples R China;
推荐引用方式 GB/T 7714	Liu, Xia,Xu, Zhijian,Hou, Chuanwei,et al. Inhibition of hepatitis B virus replication by targeting ribonucleotide reductase M2 protein[J]. BIOCHEMICAL PHARMACOLOGY,2016,103:118-128.
APA	Liu, Xia.,Xu, Zhijian.,Hou, Chuanwei.,Wang, Meng.,Chen, Xinhuan.,...&Shao, Jimin.(2016).Inhibition of hepatitis B virus replication by targeting ribonucleotide reductase M2 protein.BIOCHEMICAL PHARMACOLOGY,103,118-128.
MLA	Liu, Xia,et al."Inhibition of hepatitis B virus replication by targeting ribonucleotide reductase M2 protein".BIOCHEMICAL PHARMACOLOGY 103(2016):118-128.