Strong antiviral activity of the new l-hydroxycytidine derivative, l-Hyd4FC, in

StephenW

http://www.ncbi.nlm.nih.gov/pubmed/22368233
Antivir Ther. 2012 Feb 27. doi: 10.3851/IMP2075. [Epub ahead of print]
Strong antiviral activity of the new l-hydroxycytidine derivative, l-Hyd4FC, in HBV-infected human chimeric uPA/SCID mice.Volz T, Lütgehetmann M, Allweiss L, Warlich M, Bierwolf J, Pollok JM, Petersen J, Matthes E, Dandri M.
Source
Department of Internal Medicine, University Medical Center Hamburg, Hamburg, Germany.

Abstract
BACKGROUND: Suppression of viral replication with nucleoside/nucleotide inhibitors has been shown to greatly improve the outcome of chronic HBV infection. β-l-nucleoside analogues, especially β-l-deoxycytidine derivatives represent one of the most efficient groups of antiretroviral compounds. We recently described that hydroxylation of the amino group of these β-l-deoxycytidine derivatives preserved their strong HBV inhibitory activity in vitro, but strongly reduced their cytotoxicity. From this new group of compounds we selected β-l-2',3'-didehydro-2',3'-dideoxy-N(4)-hydroxy-5-fluorocytidine (l-Hyd4FC) for a first in vivo investigation. The aim of this study was to determine the antiviral activity of l-Hyd4FC in HBV-infected human liver chimeric urokinase plasminogen activator (uPA)/SCID mice.
METHODS: Stably infected animals (median 6×10(7) HBV DNA/ml) were injected daily with either l-Hyd4FC (50 mg/kg) or saline as controls. Mice treated with lamivudine served to compare the in vivo antiviral potency of l-Hyd4FC. Virological changes were determined by quantitative PCR.
RESULTS: Treatment with l-Hyd4FC for 4 weeks induced a 2-log reduction of viraemia, while a median 1.5-log decline was achieved with lamivudine. Intrahepatically, l-Hyd4FC induced a median eightfold decline of viral activity (relaxed circular DNA/covalently closed circular DNA), and threefold reduction of pregenomic RNA/GAPDH levels. No significant decline of subgenomic HBV transcripts, as well as of circulating hepatitis B e antigen and hepatitis B surface antigen was detected. Maintenance of human serum albumin concentrations throughout the study, negative TUNEL staining and occurrence of viral rebound after drug withdrawal indicated that l-Hyd4FC was not toxic in human hepatocytes.
CONCLUSIONS: Administration of l-Hyd4FC in uPA/SCID mice harbouring HBV-infected human hepatocytes demonstrated the high antiviral potency of this drug in vivo. Such characteristics make l-Hyd4FC a good candidate for further investigations a as potential HBV therapeutic agent.

StephenW

中病毒疗法。 2012年二月27日。 DOI：10.3851/IMP2075。 [出处提前打印]
新的L-hydroxycytidine衍生，L-Hyd4FC在HBV感染的人鼠嵌合UPA / SCID小鼠，强大的抗病毒活性。
福尔茨ţ，Lütgehetmann中号，大号Allweiss，Warlich，彼得森Pollok JM Bierwolf J，J，Matthesé，Dandri研究
源

内科，德国汉堡大学医学中心的汉堡。
抽象
背景：

抑制病毒复制的核苷/核苷酸抑制剂已被证明，大大提高了慢性乙肝病毒感染的结果。 β-L-核苷类似物，尤其是β-L-脱氧衍生物的最有效的抗逆转录病毒化合物的群体之一。最近，我们描述了这些β-L-脱氧衍生物的氨基酸组保留其强劲的乙肝病毒在体外抑制活性的羟化，但其细胞毒性大大减少。从我们选择了这组新的化合物β-L-2'，3'-脱氢-2'，3'-脱氧-N的（4） - 羟基-5  - 氟胞苷（L-Hyd4FC）在体内的调查。本研究的目的是确定的L-Hyd4FC在乙肝病毒感染人体肝嵌合尿激酶型纤溶酶原激活剂（uPA）/ SCID小鼠的抗病毒活性。
方法：

稳定感染的动物（中位数为6×10（7）HBV DNA /毫升）每天注射要么Hyd4FC（L-50毫克/千克）或生理盐水作为对照。拉米夫定治疗小鼠担任比较L-Hyd4FC体内抗病毒效力。定量PCR病毒学的变化进行了测定。
结果：

L-Hyd4FC 4周的治疗诱导2日志减少了病毒血症，而中位数下降1.5日志与拉米夫定实现。 intrahepatically，L-Hyd4FC病毒活性的诱导八倍下降中位数（宽松的环状DNA /共价闭合环状DNA），并减少三倍的前基因组RNA的/ GAPDH的水平。没有显着下降的乙肝病毒亚基因组成绩单，以及循环乙肝e抗原和乙肝表面抗原检测。维护人血清白蛋白浓度在整个研究，TUNEL染色阴性，停药后病毒反弹的发生表明，L-Hyd4FC是不是在人类肝细胞毒性。
结论：

中uPA / SCID的窝藏HBV感染人体肝细胞的小鼠L-Hyd4FC的政府证明这种药物在体内的抗病毒效力。这些特点使L-Hyd4FC一个很好的候选人作为潜在的乙肝治疗剂作进一步调查。

9病成医

请高手简单解释一下啊.