摘要
[背景]蛋白酶在病毒生命周期中扮演着关键角色,参与病毒的复制、组装和成熟等过程,是抗病毒药物的重要靶点.随着对病毒蛋白酶结构和功能的深入研究,其抑制剂、蛋白水解靶向嵌合体等已成为抗病毒药物研发的重要方向.[进展]结构生物学和药物化学技术飞速发展,多种病毒蛋白酶抑制剂的研究取得显著进展.本文总结新型冠状病毒、肠道病毒71型、丙型肝炎病毒和人类免疫缺陷病毒这几种致病病毒蛋白酶的结构功能特点与抑制剂设计的研究进展,讨论针对蛋白酶药物设计的策略.[展望]基于蛋白酶结构的抗病毒药物研发前景广阔,但同时也面临诸多挑战.病毒易发生变异、蛋白酶的三维结构解析困难等问题增加了研发有效抗病毒药物的难度,人工智能技术或能为这些挑战带来机遇.
[Background]Viral proteases are a class of enzymes encoded by viral genomes that hydrolyze peptide bonds in protein substrates.As essential enzymes in the viral life cycle,proteases play pivotal roles in viral polyprotein processing,replication,assembly,and maturation.In addition,viral proteases exhibit high sequence and structural conservation across different strains of the same virus,and even share certain similarities among proteases from different viruses.These characteristics make them attractive and reliable targets for the development of broad-spectrum antiviral drug.Over the past few decades,extensive research has focused on understanding the structural and functional properties of these enzymes.The previous research has enabled the development of multiple classes of antiviral compounds specifically targeting these essential viral enzymes,including protease inhibitors and proteolysis-targeting chimeras(PROTACs).These compounds achieve their antiviral activity by either directly blocking the catalytic activity of viral proteases or inducing their degradation,thereby effectively suppressing viral propagation.[Progress]This review first summarizes recent advances in the structural and functional characterization of proteases from several key pathogenic viruses,including severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),enterovirus 71(EV71),hepatitis C virus(HCV),and human immunodeficiency virus(HIV).Breakthroughs in structural biology,particularly techniques such as X-ray crystallography and cryo-electron microscopy,have enabled high-resolution structural elucidation of these viral proteases,providing crucial insights into their catalytic mechanisms and substrate specificity.For instance,the structural determination of SARS-CoV-2 main protease facilitated the development of the antiviral oral drug nirmatrelvir.Furthermore,this review provides a systematic analysis of recent advances in antiviral protease inhibitors.Based on their structural characteristics,these inhibitors can be broadly categorized into three major classes:peptidomimetics,non-peptidic compounds,and natural product derivatives.Peptidomimetic inhibitors are designed to mimic the peptide substrate structure of viral proteases,incorporating modified amino acid analogs that specifically bind to the enzyme s active site,thereby inhibiting catalytic activity.These inhibitors often exhibit high selectivity by leveraging the protease s natural substrate recognition mechanism.Non-peptidic inhibitors,in contrast,deviate from traditional peptide scaffolds and instead interact with either the active site or allosteric pockets of proteases,inducing conformational changes that impair substrate binding or enzymatic function.Compared with peptidomimetic inhibitors,non-peptidic inhibitors offers advantages in metabolic stability and oral bioavailability.Natural product-derived inhibitors are structurally optimized versions of bioactive compounds isolated from natural sources,combining inherent antiviral properties with improved pharmacokinetic profiles through rational chemical modifications.Additionally,this review also discusses novel structure-based drug design approaches targeting these viral proteases,including:1)allosteric inhibitors that bind to regulatory sites distal from the catalytic center to disrupt protease function;2)dual-target inhibitors capable of simultaneously interfering with multiple key steps in viral replication;and 3)PROTACs that hijack the host ubiquitin-proteasome system for selective degradation of viral proteases.These innovative strategies provide new avenues to address drug resistance and improve therapeutic specificity.Finally,we summarize the key aspects of this review and discuss the current challenges in the field of antiviral drugs development based on the structure of proteases.[Perspective]While structure-based antiviral drug development holds great promise,it also presents considerable challenges.For instance,the high mutability of viruses,technical difficulties in resolving protease 3D structures,and the need to optimize the safety and bioavailability of existing inhibitors hinder the development of effective therapeutics.Artificial intelligence(AI)may offer innovative solutions to overcome these hurdles.AI-driven structural biology tools,such as AlphaFold and RoseTTAFold are accelerating protease modeling,while predictive algorithms enable rapid analysis of mutational effects and drug resistance analysis.Molecular optimization has also been transformed by AI modeling,which enables comprehensive optimization of drug properties,including bioactivity,safety profiles,and pharmacokinetics.These developments suggest a paradigm shift toward computationally accelerated drug discovery.
作者
王婧
陈嘉馨
张源元
尚鲁庆
WANG Jing;CHEN Jiaxin;ZHANG Yuanyuan;SHANG Luqing(State Key Laboratory of Medicinal Chemical Biology,College of Pharmacy,Nankai University,Tianjin 300350,China)
出处
《厦门大学学报(自然科学版)》
北大核心
2026年第1期1-15,共15页
Journal of Xiamen University:Natural Science
基金
国家自然科学基金(22177055)
国家重点研发计划(2022YFC2303300)。
关键词
病毒蛋白酶
蛋白酶抑制剂
抗病毒药物研发
人工智能
viral protease
protease inhibitor
antiviral drug development
artificial intelligence
