最新药概念: Phenylpropenamide Derivative AT-130

liver411

[B]~非核苷病毒复制阻碍剂[/B]

(谢谢大家能够帮助大家翻译)

[B]The Phenylpropenamide Derivative AT-130 Inhibits HBV Replication at Viral Encapsidation and Packaging[/B]

Nucleoside reverse transcriptase inhibitors (NRTI) are the most common agents under study for chronic HBV. These include Epivir-HBV (FDA-approved) and the experimental agents entecavir, Coviracil, (emtricitabine), DAPD, L-FMAU, LdT, and ACH-443. The nucleotide Hepsera (adefovir dipivoxil) is also FDA-approved.

At the 53rd AASLD, researchers reported on promising laboratory testing of AT-130, a novel a non-nucleoside inhibitor of HBV replication. Following is a summary of their laboratory testing results:

Background: Nucleoside analogue antiviral therapy for chronic HBV infection has proven to be effective in the short term. However, the rapid development of resistance limits its clinical utility.

Nucleoside analogues block HBV replication by inhibiting the viral reverse transcriptase. Agents targeting other stages of viral replication are greatly needed in order to develop improved combination therapies.

The phenylpropenamide derivatives AT-61 and AT-130 have been shown to inhibit HBV replication in vitro (King et al 1998 AAC 42:3179). The site of action of these compounds remains undefined.

Aim: To determine the mechanism of action of AT-130, a non-nucleoside inhibitor of HBV replication.

Methods: Hep G-2 cells were transduced with genotype D HBV using the recombinant HBV baculovirus system. The production of HBV replicative intermediates was assessed in the presence and absence of AT-130. After 7 days, cells were harvested and processed for HBV total DNA, encapsidated DNA, extra-cellular virion DNA, total RNA, encapsidated RNA and core protein levels.

Assays for HBV DNA polymerase activity were also performed in the presence or absence of AT-130. A HBV packaging cell line consisting of Huh-7 cells stably transfected with a tetracycline-responsive expression vector which supplies the HBV core protein in trans were transiently transfected with either an infectious wild-type plasmid or a defective core-stop codon mutant plasmid of the HBV genome in the presence and absence of AT-130. The packaging reaction as well as the production of viral DNA and core protein were again measured.

Results: AT-130 inhibited HBV DNA replication in transduced cells but had no effect on viral DNA polymerase activity or core protein translation. Total HBV RNA production was also unaffected in the presence of the drug whilst the amount of encapsidated RNA was significantly reduced, indicating that AT 130 functions as a packaging inhibitor.

To confirm this mechanism, the trans packaging cell line system was used in which the defective core stop HBV mutant plasmid was transfected into the Huh-7 cells expressing core protein. In the absence of AT-130 there was rescue of the HBV core stop codon mutant. In the presence of AT-130, packaging was inhibited with no encapsidation of HBV RNA and without core protein production being affected.

Conclusion: The phenylpropenamide derivative AT-130 effectively inhibited HBV replication in vitro at the level of packaging of the pregenomic RNA into core particles and thereby inhibited subsequent viral reverse transcription. This is the first demonstration of inhibition of HBV genome replication by a non-nucleoside analogue acting at the level of viral encapsidation and packaging.

01/13/03

Reference
J Feld and others. THE PHENYLPROPENAMIDE DERIVATIVE AT-130 INHIBITS HBV REPLICATION AT VIRAL ENCAPSIDATION AND PACKAGING. Abstract 549. Abstract 223. 53rd AASLD. November 1-5, 2002. Boston, MA. Hepatology 2002: Vol 36 No 4, Pt 2 of 2.

hchu

我不会译，想用金山快译顶一下，又觉得形同捣乱。谁有空译一下吧，一篇也好。别弄到411往后不再找新东西了。

silence

~非核苷病毒复制阻碍剂 AT-130

还在实验室阶段
目前。 抑制病毒复制。 多为核苷类似物如拉米，阿迪夫为

AT-130 不是核苷类似物。

98年就有该药能在体外抑制病毒复制的报道
（AT-61 and AT-130 have been shown to inhibit HBV replication in vitro (King et al 1998 AAC 42:3179). Th）

2002年 53届AASLD报道了该药作用机制的研究

提示 该药作用机理为

在病毒包装水平（packaging）上发挥作用
抑制乙肝前基因组RNA组装成病毒颗粒。

这是这种机制发现的第一种药物

Conclusion: The phenylpropenamide derivative AT-130 effectively inhibited HBV replication in vitro at the level of packaging of the pregenomic RNA into core particles and thereby inhibited subsequent viral reverse transcription. This is the first demonstration of inhibition of HBV genome replication by a non-nucleoside analogue acting at the level of viral encapsidation and packaging.

rui193736

“在病毒包装水平（packaging）上发挥作用
抑制乙肝前基因组RNA组装成病毒颗粒。

这是这种机制发现的第一种药物”
请专家解释一下，这种药对CCCDNA有没有减少的作用？

九阴真君

好像不能

九阴真君

好像不能