新型二氢嘧啶衍生物作为HBV衣壳蛋白抑制剂的设计、合成和评价

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2025-07-19 DOI:10.1016/j.bmc.2025.118320

Xiaodan Qiu , Shengnan Zhao , Ya Wang , Kun Xiao , Yitong Liu , Yuhuan Li , Shuo Wu , Qingguo Meng , Guangzhi Shan

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引用次数: 0

摘要

衣壳的组装是乙型肝炎病毒（HBV）生命周期的关键阶段。衣壳蛋白组装抑制剂可以特异性靶向HBV衣壳的形成，从而破坏其组装并发挥抗病毒作用。本研究通过对溶剂暴露区进行修饰，合成了4个系列共40个二氢嘧啶衍生物。结果表明，化合物I-3e具有较强的抗hbv活性（EC50 = 0.033±0.012 μM）。机制研究表明，该化合物可以剂量依赖性地抑制HBc蛋白和衣壳蛋白的水平。表面等离子体共振和分子对接证实了I-3e与靶蛋白之间的相互作用。此外，对I-3e性质的预测表明，它符合Lipinski的五项规则，并有望具有与GLS4相似的药代动力学特征。本研究为发现有效的HBV衣壳蛋白组装抑制剂奠定了基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Design, synthesis and evaluation of new dihydropyrimidine derivatives as HBV capsid protein inhibitors

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Design, synthesis and evaluation of new dihydropyrimidine derivatives as HBV capsid protein inhibitors

The assembly of the capsid is a critical phase in the lifecycle of the hepatitis B virus (HBV). Capsid protein assembly inhibitors can specifically target HBV capsid formation, thereby disrupting its assembly and exerting antiviral effects. In this study, a total of 40 dihydropyrimidine derivatives across four series were synthesized by the modification of solvent-exposed region. The results indicated that compound I-3e exhibited potent anti-HBV activity (EC₅₀ = 0.033 ± 0.012 μM). Mechanistic studies revealed that this compound can dose-dependently inhibit levels of both HBc proteins and capsid proteins. Surface plasmon resonance and molecular docking confirmed the interactions between I-3e and the target protein. Furthermore, predictions regarding the properties of I-3e suggested it aligns well with Lipinski's five rules and is anticipated to possess pharmacokinetic characteristics similar to those of GLS4. This research lays a foundation for discovering effective HBV capsid protein assembly inhibitors.

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.