发现新型乙型肝炎病毒核衣壳组装抑制剂

StephenW

ACS Infect Dis. 2018 Dec 10. doi: 10.1021/acsinfecdis.8b00269. [Epub ahead of print]
Discovery of novel hepatitis B virus nucleocapsid assembly inhibitors.
Zhang X, Cheng J, Ma J, Hu Z, Wu S, Hwang N, Kulp J, Du Y, Guo JT, Chang J.
Abstract

Hepatitis B virus (HBV) core protein is a small protein with 183 amino acid residues and assembles the pre-genomic (pg) RNA and viral DNA polymerase to form nucleocapsids. During the last decades, several groups have reported HBV core protein allosteric modulators (CpAMs) with distinct chemical structures. CpAMs bind to the hydrophobic HAP pocket located at the dimer-dimer interface and induce allosteric conformational changes in the core protein subunits. While type I CpAMs, heteroaryldihydropyrimidine (HAP) derivatives, misdirect core protein dimers to assemble non-capsid polymers, Type II CpAMs, represented by sulfamoylbenzamides, phenylpropenamides and several other chemotypes, induce the assembly of empty capsids with global structural alterations and faster mobility in native agarose gel electrophoresis. Through high throughput screening of an Asinex small molecule library containing 19,920 compounds, we identified 8 structurally distinct CpAMs. While 7 of those compounds are typical Type II CpAMs, a novel benzamide derivative, designated as BA-53038B, induced the formation of morphologically "normal" empty capsids with slow electrophoresis mobility. Drug resistant profile analyses indicated that BA-53038B most likely bound to the HAP pocket, but obviously modulated HBV capsid assembly in a distinct manner. BA-53038B and other CpAMs reported herein provide novel structure scaffolds for the development of core protein-targeted antiviral agents for the treatment of chronic hepatitis B.

PMID:
    30525438
DOI:
    10.1021/acsinfecdis.8b00269

StephenW

ACS Infect Dis。 2018年12月10日doi：10.1021 / acsinfecdis.8b00269。 [提前打印]
发现新型乙型肝炎病毒核衣壳组装抑制剂。
张,,程杰，马杰，胡,,吴,,黄N，Kulp J，杜,,郭JT，张杰
抽象

乙型肝炎病毒（HBV）核心蛋白是一种含有183个氨基酸残基的小蛋白，可组装前基因组（pg）RNA和病毒DNA聚合酶，形成核衣壳。在过去几十年中，几个研究小组报告了具有不同化学结构的HBV核心蛋白质变构调节剂（CpAM）。 CpAM结合位于二聚体 - 二聚体界面的疏水性HAP袋并诱导核心蛋白亚基中的变构构象变化。虽然I型CpAMs，杂芳基二氢嘧啶（HAP）衍生物，错误的核心蛋白质二聚体组装非衣壳聚合物，II型CpAMs，以氨磺酰苯甲酰胺，苯丙烯酰胺和其他几种化学型为代表，诱导空衣壳的组装，具有全局结构改变和更快的流动性。天然琼脂糖凝胶电泳。通过对包含19,920种化合物的Asinex小分子文库的高通量筛选，我们鉴定了8​​种结构上不同的CpAM。虽然这些化合物中的7种是典型的II型CpAM，但是新的苯甲酰胺衍生物（称为BA-53038B）诱导形成具有缓慢电泳迁移率的形态学“正常”空衣壳。耐药谱分析表明BA-53038B最可能与HAP袋结合，但明显以明显的方式调节HBV衣壳组装。本文报道的BA-53038B和其他CpAM提供了用于开发用于治疗慢性乙型肝炎的核心蛋白靶向抗病毒剂的新型结构支架。

结论：
    30525438
DOI：
    10.1021 / acsinfecdis.8b00269
ACS Infect Dis. 2018 Nián 12 yuè 10 rì doi:10.102

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