Epi-Cyclophellitol Cyclosulfate, a Mechanism-Based Endoplasmic Reticulum α-Glucosidase II Inhibitor, Blocks Replication of SARS-CoV-2 and Other Coronaviruses
Melissa Thaler, Tim P. Ofman, Ken Kok, Jurriaan J. A. Heming, Elisha Moran, Isabelle Pickles, Anouk A. Leijs, Adrianus M. C. H. van den Nieuwendijk, Richard J. B. H. N. van den Berg, Gijs Ruijgrok, Zachary Armstrong, Clarisse Salgado-Benvindo, Dennis K. Ninaber, Eric J. Snijder, Constant A. A. van Boeckel, Marta Artola, Gideon J. Davies, Herman S. Overkleeft, Martijn J. van Hemert
{"title":"Epi-Cyclophellitol Cyclosulfate, a Mechanism-Based Endoplasmic Reticulum α-Glucosidase II Inhibitor, Blocks Replication of SARS-CoV-2 and Other Coronaviruses","authors":"Melissa Thaler, Tim P. Ofman, Ken Kok, Jurriaan J. A. Heming, Elisha Moran, Isabelle Pickles, Anouk A. Leijs, Adrianus M. C. H. van den Nieuwendijk, Richard J. B. H. N. van den Berg, Gijs Ruijgrok, Zachary Armstrong, Clarisse Salgado-Benvindo, Dennis K. Ninaber, Eric J. Snijder, Constant A. A. van Boeckel, Marta Artola, Gideon J. Davies, Herman S. Overkleeft, Martijn J. van Hemert","doi":"10.1021/acscentsci.4c00506","DOIUrl":null,"url":null,"abstract":"The combined inhibition of endoplasmic reticulum (ER) α-glucosidases I and II has been shown to inhibit replication of a broad range of viruses that rely on ER protein quality control. We found, by screening a panel of deoxynojirimycin and cyclitol glycomimetics, that the mechanism-based ER α-glucosidase II inhibitor, 1,6-<i>epi</i>-cyclophellitol cyclosulfate, potently blocks SARS-CoV-2 replication in lung epithelial cells, halting intracellular generation of mature spike protein, reducing production of infectious progeny, and leading to reduced syncytium formation. Through activity-based protein profiling, we confirmed ER α-glucosidase II inhibition in primary airway epithelial cells, grown at the air–liquid interface. 1,6-<i>epi</i>-Cyclophellitol cyclosulfate inhibits early pandemic and more recent SARS-CoV-2 variants, as well as SARS-CoV and MERS-CoV. The reported antiviral activity is comparable to the best-in-class described glucosidase inhibitors, all competitive inhibitors also targeting ER α-glucosidase I and other glycoprocessing enzymes not involved in ER protein quality control. We propose selective blocking ER-resident α-glucosidase II in a covalent and irreversible manner as a new strategy in the search for effective antiviral agents targeting SARS-CoV-2 and other viruses that rely on ER protein quality control.","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":null,"pages":null},"PeriodicalIF":12.7000,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Central Science","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1021/acscentsci.4c00506","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
The combined inhibition of endoplasmic reticulum (ER) α-glucosidases I and II has been shown to inhibit replication of a broad range of viruses that rely on ER protein quality control. We found, by screening a panel of deoxynojirimycin and cyclitol glycomimetics, that the mechanism-based ER α-glucosidase II inhibitor, 1,6-epi-cyclophellitol cyclosulfate, potently blocks SARS-CoV-2 replication in lung epithelial cells, halting intracellular generation of mature spike protein, reducing production of infectious progeny, and leading to reduced syncytium formation. Through activity-based protein profiling, we confirmed ER α-glucosidase II inhibition in primary airway epithelial cells, grown at the air–liquid interface. 1,6-epi-Cyclophellitol cyclosulfate inhibits early pandemic and more recent SARS-CoV-2 variants, as well as SARS-CoV and MERS-CoV. The reported antiviral activity is comparable to the best-in-class described glucosidase inhibitors, all competitive inhibitors also targeting ER α-glucosidase I and other glycoprocessing enzymes not involved in ER protein quality control. We propose selective blocking ER-resident α-glucosidase II in a covalent and irreversible manner as a new strategy in the search for effective antiviral agents targeting SARS-CoV-2 and other viruses that rely on ER protein quality control.
环硫酸表黄柏醇--一种基于机制的内质网α-葡萄糖苷酶 II 抑制剂--阻断了 SARS-CoV-2 和其他冠状病毒的复制
研究表明,联合抑制内质网(ER)α-葡萄糖苷酶 I 和 II 可抑制依赖ER蛋白质量控制的多种病毒的复制。通过筛选脱氧野尻霉素和环黄腐醇拟糖体,我们发现基于机制的ER α-葡萄糖苷酶II抑制剂--1,6-表环黄腐醇环硫酸盐能有效阻断肺上皮细胞中SARS-CoV-2的复制,阻止细胞内成熟尖峰蛋白的生成,减少感染性后代的产生,并减少合胞体的形成。通过基于活性的蛋白质分析,我们证实了ER α-葡萄糖苷酶 II 对在气液界面生长的原发性气道上皮细胞的抑制作用。1,6-epi-Cyclophellitol cyclosulfate 可抑制早期大流行和近期的 SARS-CoV-2 变体,以及 SARS-CoV 和 MERS-CoV。所报告的抗病毒活性与同类最佳的葡萄糖苷酶抑制剂相当,所有竞争性抑制剂也都针对 ER α-葡萄糖苷酶 I 和其他不参与 ER 蛋白质控制的糖加工酶。我们建议以共价和不可逆的方式选择性阻断驻留在ER的α-葡萄糖苷酶II,作为寻找有效抗病毒药物的新策略,以对付SARS-CoV-2和其他依赖ER蛋白质量控制的病毒。
期刊介绍:
ACS Central Science publishes significant primary reports on research in chemistry and allied fields where chemical approaches are pivotal. As the first fully open-access journal by the American Chemical Society, it covers compelling and important contributions to the broad chemistry and scientific community. "Central science," a term popularized nearly 40 years ago, emphasizes chemistry's central role in connecting physical and life sciences, and fundamental sciences with applied disciplines like medicine and engineering. The journal focuses on exceptional quality articles, addressing advances in fundamental chemistry and interdisciplinary research.