摘要
乙型肝炎病毒(hepatitis B virus,HBV)感染是全球性健康挑战,现有药物如聚乙二醇干扰素类和核苷类似物存在长期用药毒性、病毒易产生耐药性及无法清除共价闭合环状DNA(covalently closed circular DNA,cccDNA)等局限。核心蛋白变构调节剂(core protein allosteric modulators,CpAMs)作为新型抗HBV药物,通过靶向HBcAg干扰衣壳组装,不仅能阻断病毒核衣壳形成,抑制病毒复制,还可间接影响cccDNA库稳定性,且具有相对高的耐药屏障。本文系统分析HBV对CpAMs的耐药性,提出核苷类似物联合CpAMs、强化蛋白-药物相互作用、靶向降解HBcAg、设计多靶点抑制剂及联合用药等抗耐药策略。未来,结构生物学、计算化学与免疫疗法的融合为开发高效低耐药的新型抑制剂提供思路,推动乙肝功能性治愈。
Hepatitis B virus(HBV)infection represents a significant global health challenge.Current therapeutic options,such as interferon and nucleoside analogues(NAs),are limited by issues including long-term medication toxicity,the virus's propensity to develop drug resistance,and the inability to eradicate covalently closed circular DNA(cccDNA).Core protein allosteric modulators(CpAMs),as an emerging class of anti-HBV drugs,target HBcAg to interfere with capsid assembly.This not only blocks viral nucleocapsid formation and inhibits viral replication but also indirectly destabilizes the cccDNA pool,while exhibiting a relatively high genetic barrier to resistance.This article systematically evaluates HBV drug resistance to CpAMs and proposes anti-resistance strategies,including the combination of nucleoside analogues with CpAMs,enhancing protein-drug interactions,targeting HBcAg degradation,designing multi-target inhibitors,and employing combination therapy.Looking ahead,the integration of structural biology,computational chemistry,and immunotherapy will offer innovative approaches for developing novel,highly effective,and low-resistance inhibitors,thereby advancing the functional cure of hepatitis B.
作者
杨泽春
刘媛媛
梁明辉
王鹤望
杨洁
展鹏
贾海永
YANG Zechun;LIU Yuanyuan;LIANG Minghui;WANG Hewang;YANG Jie;ZHAN Peng;JIA Haiyong(School of Pharmacy,Shandong Second Medical University,Weifang 261053;Qingzhou People's Hospital,Weifang 262500;School of Pharmacy,Shandong University,Jinan 250012,China)
出处
《中国药科大学学报》
北大核心
2025年第6期700-709,I0004,共11页
Journal of China Pharmaceutical University
基金
国家重点研发计划项目(No.2023YFC2606500)
国家自然科学基金项目(No.81903468)
山东第二医科大学大学生创新创业训练计划项目(X2024121)
潍坊市科技发展计划项目(No.2023YX038)。
关键词
乙肝病毒
核心蛋白变构调节剂
耐药性
抗耐药策略
hepatitis B virus
core protein allosteric modulators
drug resistance
strategies to combat drug resistance
