摘要
金属离子依赖性蛋白在病毒复制、组装和宿主细胞侵袭等关键环节中发挥着核心作用,使其成为抗病毒治疗策略的理想靶点.从药物化学的角度出发,综述了2021-2023年,以金属离子依赖性蛋白为靶标的抗病毒药物研究的新进展.详细分析了人类免疫缺陷病毒、人类巨细胞病毒、乙型肝炎病毒、流感病毒、裂谷热病毒、严重急性呼吸综合征冠状病毒等重要病毒的金属离子依赖性蛋白抑制剂,探讨了这些抑制剂的药理活性、作用机制及临床应用潜力.同时强调了设计病毒金属酶抑制剂面临的挑战,如确保高度选择性和特异性、药物稳定性、生物利用度等,以及应对病毒高变异率导致的耐药性问题.最后总结了抗病毒药物研发的新趋势,包括结构基础药物设计、高通量筛选、片段生长和多位点结合策略等,为开发新型高效低毒抗病毒药物提供了新的思路和方法.
Abstract
Metalloproteins,which play a central role in key processes such as viral replication,assembly,and invasion of host cells,have emerged as ideal targets for antiviral drug design.This article provides a comprehensive review of the latest advances(2021-2023)in antiviral drug research targeting metalloproteins from the perspective of medicinal chemistry,meticulously analyzing metalloprotein inhibitors for important viruses including HIV-1,HCMV,HBV,IFV,RVFV,and SARS-CoV-2,discussing their pharmacological activity,mechanisms of action,and potential for clinical application,addressing the challenges in designing viral metalloenzyme inhibitors,including ensuring high selectivity and specificity,drug stability,bioavailability,and combating drug resistance arising from the high mutation rates of viruses,and summarizing the emerging trends in antiviral drug development,including structure-based drug design,high-throughput screening,fragment growth and multi-site binding strategies,aiming to provide some new avenues and methodologies for the development of novel antiviral drugs that are both potent and less toxic.
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