合成4-氧代四氢嘧啶-1（2H）-羧酰胺衍生物作为乙型肝炎病毒

StephenW

Synthesis of 4-oxotetrahydropyrimidine-1(2H)-carboxamides derivatives as capsid assembly modulators of hepatitis B virus
Nicky Hwang #  1 , Haiqun Ban #  1   2 , Junjun Chen  1 , Julia Ma  1 , Hui Liu  1   3 , Patrick Lam  1 , John Kulp  1 , Stephan Menne  4 , Jinhong Chang  1 , Ju-Tao Guo  1 , Yanming Du  1
Affiliations
Affiliations

    1
    Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA 18902 USA.
    2
    Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1630 Dongfang Road, Shanghai, 200127 Pudong New District China.
    3
    Department of Pathogen Biology, Peking University Medical Center, Beijing, China.
    4
    Georgetown University Medical Center, 3900 Reservoir Road, Washington, DC 20057 USA.

#
Contributed equally.

    PMID: 33456291 PMCID: PMC7797712 DOI: 10.1007/s00044-020-02677-3

Abstract

We report herein the synthesis and evaluation of phenyl ureas derived from 4-oxotetrahydropyrimidine as novel capsid assembly modulators of hepatitis B virus (HBV). Among the derivatives, compound 27 (58031) and several analogs showed an activity of submicromolar EC50 against HBV and low cytotoxicities (>50 μM). Structure-activity relationship studies revealed a tolerance for an additional group at position 5 of 4-oxotetrahydropyrimidine. The mechanism study indicates that compound 27 (58031) is a type II core protein allosteric modulator (CpAMs), which induces core protein dimers to assemble empty capsids with fast electrophoresis mobility in native agarose gel. These compounds may thus serve as leads for future developments of novel antivirals against HBV.

Keywords: 4-Oxotetrahydropyrimidine; Capsid assembly; Hepatitis B virus; Phenyl ureas.

© The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature 2021.

StephenW

合成4-氧代四氢嘧啶-1（2H）-羧酰胺衍生物作为乙型肝炎病毒的衣壳装配调节剂
黄家琪＃1，海群版＃1 2，陈俊俊1，马朱莉娅1，刘慧1 3，林冠希1，约翰·库尔普1，斯蒂芬·曼妮4，张进宏1，郭菊涛1，杜艳明1
隶属关系
隶属关系

    1个
    Baruch S.Blumberg研究所，3805 Old Easton Road，Doylestown，PA 18902美国。
    2
    中国上海浦东新区东方路1630号上海交通大学医学院附属仁济医院，上海200127。
    3
    北京大学医学中心病原生物学教研室，北京
    4
    乔治敦大学医学中心，水库路3900号，华盛顿特区，美国20057。

＃
贡献均等。

    PMID：33456291 PMCID：PMC7797712 DOI：10.1007 / s00044-020-02677-3

抽象

我们在此报告了衍生自4-氧代四氢嘧啶的苯基脲类化合物的合成和评估，所述苯基脲是乙型肝炎病毒（HBV）的新型衣壳装配调节剂。在衍生物中，化合物27（58031）和几种类似物表现出亚微摩尔EC50的抗HBV活性和低细胞毒性（> 50μM）。结构活性关系研究表明，对4-氧代四氢嘧啶第5位的另一个基团具有耐受性。机理研究表明，化合物27（58031）是II型核心蛋白变构调节剂（CpAM），它诱导核心蛋白二聚体组装天然衣壳糖凝胶中具有快速电泳迁移率的空衣壳。因此，这些化合物可作为未来针对HBV的新型抗病毒药开发的先导。

关键字：4-氧四氢嘧啶；衣壳装配；乙型肝炎病毒;苯基脲。

©作者，根据Springer Nature 2021的一部分获得Springer Science + Business Media，LLC的独家许可。

StephenW

https://link.springer.com/conten ... 044-020-02677-3.pdf