EASL2012:Inhibition of Hepatitis B Virus Replication In Vivo by A Novel non-nucl

StephenW

Abstract               
                                

Title	Inhibition of Hepatitis B Virus Replication In Vivo by A Novel non-nucleosidic compound
Speaker:	Xueyan   Wang
Author:	X. Wang*, D. Jiang, H. Zhang, F. Liu, H. Zhang, X. Xie, L. Wei, H. Chen
Affiliation:	Peking University People's Hospital, Peking University Hepatology Institute, Beijing, China. *[email protected]
Background and aims: Chronic hepatitis B virus (HBV) infection is a major cause of liver disease. The development of new antiviral compounds suitable for monotherapy or combination therapy for HBV infections is highly desired. GH-1, a member of a class of heteroaryldihydropyrimidines (HAP), was discovered a novel and highly specific anti-viral principle in vitro. Here, we reported the antiviral activity of GH-1 in transgenic mice expressing HBV. Methods: Transgenic HBV mice with a genetic background of BALB/c were used. GH-1 was administered orally twice daily for 28 days at dosages ranging from 15 to 120 mg/kg per day. HBV DNA in the liver and in the plasma was analyzed by DNA-dot-blot and quantitative PCR. Liver RNA was analyzed by Northern blot analysis. For detection hepatitis B core antigen (HBcAg), Western blot and immunohistochemistry analysis were detected. Results: The compound reduced HBV DNA in the liver and in the plasma dose-dependently with efficacy comparable to 3TC (P< 0.05). In contrast to 3TC-treated mice, we found a reduction of cytoplasmic HBcAg in liver sections of GH-1 treated mice, which indicated a different mode of action. GH-1 exerted a dose-dependent inhibition of intracellular HBV core particle formation. Conclusions: GH-1 is a new anti-HBV drug candidate for future therapeutic regimens to combat chronic HBV infection. Inhibition of HBV core particles by this drug suggested its novel mechanism of action.

StephenW

标题抑制体内B型肝炎病毒复制的一个新型非nucleosidic的复合
王主讲人：胡雪岩
作者：D.江，H.张，刘楼，H.张，谢十，属魏，H。陈王*，十
单位：北京大学人民医院，北京大学肝病研究所，北京，中国。 * [email protected]
背景和目的：慢性乙型肝炎病毒（HBV）感染是肝脏疾病的重要原因。新的适用于单一或联合治疗乙肝病毒感染的抗病毒药物的发展是非常理想的。 GH-1，一类heteroaryldihydropyrimidines（HAP）的成员，被发现在体外的小说和高度特异性的抗病毒原则。在这里，我们报道GH-1的表达HBV转基因小鼠的抗病毒活性。
方法：使用转基因乙肝病毒的BALB / c小鼠遗传背景的小鼠。 GH-1，每日两次口服剂量范围从15至120毫克/千克，每天为28天。乙肝病毒在肝脏和血浆中的DNA分析DNA点杂交和定量PCR。肝RNA进行Northern blot分析。检测乙肝核心抗原（HBcAg），Western blot和免疫组织化学分析检测。
结果：复方降低乙型肝炎病毒DNA在肝脏和血浆与疗效呈剂量依赖性与3TC（P <0.01）。在以3TC治疗的老鼠相比，我们发现在肝部分GH-1治疗的小鼠，这表明不同的行动模式的胞浆HBcAg的减少。 GH-1产生的剂量依赖性抑制细胞内HBV核心颗粒形成。
结论：GH-1是一种新的抗乙肝病毒，为今后的治疗方案，以打击慢性乙肝病毒感染的候选药物。这种药物抑制乙肝病毒核心颗粒，建议其新的作用机制。

StephenW

Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8138-43. Epub  2005 May 31.
A heteroaryldihydropyrimidine activates and can misdirect hepatitis B virus capsid assembly.Stray SJ, Bourne CR, Punna S, Lewis WG, Finn MG, Zlotnick A.
SourceDepartment of Biochemistry and Molecular Biology BRC 464, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190, USA.

AbstractHeteroaryldihydropyrimidines (HAPs) are a new class of antivirals inhibiting production of hepatitis B virus (HBV) virions in tissue culture. Here, we examine the effect of a representative HAP molecule, methyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (HAP-1), on the in vitro assembly of HBV capsid protein (Cp). HAP-1 enhances the rate and extent of Cp assembly over a broad concentration range. Aberrant particles, dominated by hexagonal arrays of Cp, were observed from assembly reactions with high HAP-1 concentrations. HAP-1 also led to dissociation of metastable HBV capsids, overcoming a kinetic barrier to dissociation by scavenging Cp and redirecting its assembly into hexamer-rich structures. Thus, HAP drugs act as allosteric effectors that induce an assembly-active state and, at high concentration, preferentially stabilize noncapsid polymers of Cp. HAP compounds may have multiple effects in vivo stemming from inappropriate assembly of Cp. These results show that activating and deregulating virus assembly may be a powerful general approach for antiviral therapeutics.

PMID:15928089 [PubMed - indexed for MEDLINE]
PMCIDMC1149411
Free PMC Article

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咬牙硬挺

很好啊！不知道效果显著否！不知道何时临床