|
 
- 现金
- 14949 元
- 精华
- 1
- 帖子
- 8576
- 注册时间
- 2008-4-12
- 最后登录
- 2024-5-6
|
本帖最后由 MP4 于 2017-5-31 00:01 编辑
HBV衣壳组装是病毒复制的一个关键步骤并且靶向HBV衣壳组装是抑制HBV的一个有前景的方向。为了发现新型 的HBV抑制剂，来自日本鹿儿岛大学等研究机构的研究人员建立了一个计算机筛查系统，该系统基于HBV核心蛋 白X射线晶体学，利用该系统研究人员将170000种化合物跟HBV核心蛋白进行了相互作用观察检测。相关结果发 表在近日在美国佐治亚州亚特兰大举办的第30届国际抗病毒研究会议(ICAR)上。
研究人员从中发现了15种化合物具有高对接分数（high docking scores），将这些化合物在HepG2.2.15.7 细 胞系中进行 HBV 复制抑制效果的测试。其中4-(4-tert-butylphenyl)-2-[(2,3-dichlorophenyl)amino]-8- methyl-3H,4H,6H-pyrimido[1,2-a][1,3,5]triazin-6-one 这几种化合物被认为可以选择性的抑制HBV复制。 它的50％有效浓度(EC50)和50％细胞毒性浓度(CC50)分别为5.3±0.4和>100 μM。该化合物能以剂量依赖的方 式限制HBV衣壳和衣壳相关HBV DNA 和RNA形成，但对HBc蛋白含量没有影响。
这些结果表明，嘧啶并三嗪酮衍生物通过阻断衣壳组装来抑制HBV复制，被认为是有希望的新型抗HBV药物。研 究人员表示现在正在进行进一步研究以优化其化学结构。http://www2.kufm.kagoshima-u.ac.jp/field/health-research/c001/01.html
http://www.isar-icar.com/resource/resmgr/docs/ICAR_2017program_FINAL.pdf
Anti-Hepatitis B Virus (HBV) Activity of Novel Pyrimidotriazinone Derivatives
Through the Inhibition of Viral Nucleocapsid Assembly
Masaaki Toyama, PhD1, Norikazu Sakakibara, PhD2, Takayuki Hamasaki, PhD1, Mika Okamoto, MD,
PhD1, Koichi Watashi, PhD3, Takaji Wakita, MD, PhD3, Masanori Baba, MD, PhD1
1Kagoshima University, Japan; 2Tokushima Bunri University, Japan; 3National Institute of Infectious Diseases, Japan
Chronic human hepatitis B virus (HBV) infection is currently treated with nucleoside analogs, including
lamivudine, entecavir, and tenofovir. They are potent inhibitors of HBV DNA polymerase, which also
functions as reverse transcriptase. Although these compounds are effective in treatment of infected
patients, emergence of drug-resistant mutants and viral reactivation after treatment interruption are still
major concerns in antiviral chemotherapy against HBV. Therefore, it is still mandatory to identify and
develop novel inhibitors that target a step other than reverse transcription in HBV replication cycle. HBV
capsid assembly is a critical step for viral replication and an attractive target for inhibition of HBV. To find
novel inhibitors of HBV, we have established an in silico screening system based on X-ray crystallography
of HBV core protein and examined 170,000 compounds for their interaction with the core protein. Fifteen
compounds with high docking scores were selected, and they were examined for their inhibitory effect
on HBV replication in HepG2.2.15.7 cells. Among them, 4-(4-tert-butylphenyl)-2-[(2,3-dichlorophenyl)
amino]-8-methyl-3H,4H,6H-pyrimido[1,2-a][1,3,5]triazin-6-one was found to be a selective inhibitor of HBV
replication. Its 50% effective concentration (EC50) and 50% cytotoxic concentration (CC50) of were 5.3±0.4
and >100 µM, respectively. The compound reduced HBV capsid formation and capsid-associated HBV DNA
and RNA in a dose-dependent fashion but did not affect the amount of HBc protein. These results indicate
that the pyrimidotriazinone derivative inhibits HBV replication through blocking the capsid assembly and
is considered to be a promising lead of novel anti-HBV agents. Further studies are in progress to optimize
their chemical structures.
|
|
发表于 2017-5-30 07:32
