Isothiafludine, a novel non-nucleoside compound, inhibits hepatitis B virus replication through blocking pregenomic RNA encapsidation

doi:10.1038/aps.2013.175

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	Isothiafludine, a novel non-nucleoside compound, inhibits hepatitis B virus replication through blocking pregenomic RNA encapsidation
	Yang, Li 2; Shi, Li-ping 2; Chen, Hai-jun 1; Tong, Xian-kun2 ; Wang, Gui-feng2 ; Zhang, Yang-ming1 ; Wang, Wen-long 1; Feng, Chun-lan 2; He, Pei-lan 2; Zhu, Feng-hua 2
刊名	ACTA PHARMACOLOGICA SINICA
	2014-03
卷号	35 期号:3 页码:410-418
关键词	hepatitis B virus replication capsid assembly pregenomic RNA non-nucleoside compound isothiafludine lamivudine adefovir entecavir
ISSN号	1671-4083
DOI	10.1038/aps.2013.175
文献子类	Article
英文摘要	Aim: To investigate the action of isothiafludine (NZ-4), a derivative of bis-heterocycle tandem pairs from the natural product leucamide A, on the replication cycle of hepatitis B virus (HBV) in vitro and in vivo. Methods: HBV replication cycle was monitored in HepG2.2.15 cells using qPCR, qRT-PCR, and Southern and Northern blotting. HBV protein expression and capsid assembly were detected using Western blotting and native agarose gel electrophoresis analysis. The interaction of pregenomic RNA (pgRNA) and the core protein was investigated by RNA immunoprecipitation. To evaluate the anti-HBV effect of NZ-4 in vivo, DHBV-infected ducks were orally administered NZ-4 (25, 50 or 100 mg.kg(-1).d(-1)) for 15 d. Results: NZ-4 suppressed intracellular HBV replication in HepG2.2.15 cells with an IC50 value of 1.33 mu mol/L, whereas the compound inhibited the cell viability with an IC50 value of 50.4 mu mol/L. Furthermore, NZ-4 was active against the replication of various drug-resistant HBV mutants, including 3TC/ETV-dual-resistant and ADV-resistant HBV mutants. NZ-4 (5, 10, and 20 mu mol/L) concentration-dependently reduced the encapsidated HBV pgRNA, resulting in the assembly of replication-deficient capsids in HepG2.2.15 cells. Oral administration of NZ-4 dose-dependently inhibited DHBV DNA replication in the DHBV-infected ducks. Conclusion: NZ-4 inhibits HBV replication by interfering with the interaction between pgRNA and HBcAg in the capsid assembly process, thus increasing the replication-deficient HBV capsids. Such mechanism of action might provide a new therapeutic strategy to combat HBV infection.
资助项目	Chinese Academy of Sciences (CAS) Knowledge Innovation Project[KSCX1-YW-10-03] ; National 863 Program Fund[2008AA02Z431] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program"[2009ZX09102-024] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program"[2012ZX09101-113]
WOS关键词	LIFE-CYCLE ; SURFACE-ANTIGEN ; NUCLEOCAPSIDS ; PROTEIN ; CELLS
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:5067885
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000332467200012
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277173]
专题	国家新药筛选中心中科院受体结构与功能重点实验室新药研究国家重点实验室药理学第一研究室
通讯作者	Nan, Fa-jun
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Chinese Natl Ctr Drug Screening, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Lab Immunopharmacol, Shanghai 201203, Peoples R China; 3.Tongji Med Coll, Tongji Hosp, Wuhan 430030, Peoples R China
推荐引用方式 GB/T 7714	Yang, Li,Shi, Li-ping,Chen, Hai-jun,et al. Isothiafludine, a novel non-nucleoside compound, inhibits hepatitis B virus replication through blocking pregenomic RNA encapsidation[J]. ACTA PHARMACOLOGICA SINICA,2014,35(3):410-418.
APA	Yang, Li.,Shi, Li-ping.,Chen, Hai-jun.,Tong, Xian-kun.,Wang, Gui-feng.,...&Zuo, Jian-ping.(2014).Isothiafludine, a novel non-nucleoside compound, inhibits hepatitis B virus replication through blocking pregenomic RNA encapsidation.ACTA PHARMACOLOGICA SINICA,35(3),410-418.
MLA	Yang, Li,et al."Isothiafludine, a novel non-nucleoside compound, inhibits hepatitis B virus replication through blocking pregenomic RNA encapsidation".ACTA PHARMACOLOGICA SINICA 35.3(2014):410-418.