{"title":"Small-Molecule Inhibition of Viral Fusion Glycoproteins.","authors":"Han-Yuan Liu, Priscilla L Yang","doi":"10.1146/annurev-virology-022221-063725","DOIUrl":null,"url":null,"abstract":"<p><p>Viral fusion glycoproteins catalyze membrane fusion during viral entry. Unlike most enzymes, however, they lack a conventional active site in which formation or scission of a specific covalent bond is catalyzed. Instead, they drive the membrane fusion reaction by cojoining highly regulated changes in conformation to membrane deformation. Despite the challenges in applying inhibitor design approaches to these proteins, recent advances in knowledge of the structures and mechanisms of viral fusogens have enabled the development of small-molecule inhibitors of both class I and class II viral fusion proteins. Here, we review well-validated inhibitors, including their discovery, targets, and mechanism(s) of action, while highlighting mechanistic similarities and differences. Together, these examples make a compelling case for small-molecule inhibitors as tools for probing the mechanisms of viral glycoprotein-mediated fusion and for viral glycoproteins as druggable targets.</p>","PeriodicalId":48761,"journal":{"name":"Annual Review of Virology","volume":null,"pages":null},"PeriodicalIF":8.1000,"publicationDate":"2021-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8543812/pdf/nihms-1743987.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annual Review of Virology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1146/annurev-virology-022221-063725","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2021/7/1 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"VIROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Viral fusion glycoproteins catalyze membrane fusion during viral entry. Unlike most enzymes, however, they lack a conventional active site in which formation or scission of a specific covalent bond is catalyzed. Instead, they drive the membrane fusion reaction by cojoining highly regulated changes in conformation to membrane deformation. Despite the challenges in applying inhibitor design approaches to these proteins, recent advances in knowledge of the structures and mechanisms of viral fusogens have enabled the development of small-molecule inhibitors of both class I and class II viral fusion proteins. Here, we review well-validated inhibitors, including their discovery, targets, and mechanism(s) of action, while highlighting mechanistic similarities and differences. Together, these examples make a compelling case for small-molecule inhibitors as tools for probing the mechanisms of viral glycoprotein-mediated fusion and for viral glycoproteins as druggable targets.
病毒融合糖蛋白在病毒进入过程中催化膜融合。然而,与大多数酶不同的是,它们缺乏催化特定共价键形成或断裂的传统活性位点。相反,它们通过高度调节的构象变化和膜变形来驱动膜融合反应。尽管将抑制剂设计方法应用于这些蛋白存在挑战,但最近对病毒融合蛋白的结构和机制的了解取得了进展,从而开发出了 I 类和 II 类病毒融合蛋白的小分子抑制剂。在此,我们回顾了经过验证的抑制剂,包括它们的发现、靶点和作用机制,同时强调了机理上的异同。总之,这些例子有力地证明了小分子抑制剂是探究病毒糖蛋白介导的融合机制的工具,也证明了病毒糖蛋白是药物靶点。
期刊介绍:
The Annual Review of Virology serves as a conduit for disseminating thrilling advancements in our comprehension of viruses spanning animals, plants, bacteria, archaea, fungi, and protozoa. Its reviews illuminate novel concepts and trajectories in basic virology, elucidating viral disease mechanisms, exploring virus-host interactions, and scrutinizing cellular and immune responses to virus infection. These reviews underscore the exceptional capacity of viruses as potent probes for investigating cellular function.