厦门大学学报（自然科学版）2026，Vol.65Issue(1)：1-15,15.DOI:10.6043/j.issn.0438-0479.202504019
基于蛋白酶结构的抗病毒药物研究进展
Research progress of antiviral drugs based on the structure of proteases
摘要
Abstract
[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.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Key words
viral protease/protease inhibitor/antiviral drug development/artificial intelligence分类
医药卫生引用本文复制引用
王婧,陈嘉馨,张源元,尚鲁庆..基于蛋白酶结构的抗病毒药物研究进展[J].厦门大学学报（自然科学版）,2026,65(1):1-15,15.基金项目
国家自然科学基金(22177055) （22177055）
国家重点研发计划(2022YFC2303300) （2022YFC2303300）
