Thaler Melissa, Ofman Tim P, Kok Ken, Heming Jurriaan J A, Moran Elisha, Pickles Isabelle, Leijs Anouk A, van den Nieuwendijk Adrianus M C H, van den Berg Richard J B H N, Ruijgrok Gijs, Armstrong Zachary, Salgado-Benvindo Clarisse, Ninaber Dennis K, Snijder Eric J, van Boeckel Constant A A, Artola Marta, Davies Gideon J, Overkleeft Herman S, van Hemert Martijn J
Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Leiden Institute of Chemistry, Leiden University, 2311 EZ Leiden, The Netherlands.
ACS Cent Sci. 2024 Jul 25;10(8):1594-1608. doi: 10.1021/acscentsci.4c00506. eCollection 2024 Aug 28.
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--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--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.
内质网（ER）α-葡萄糖苷酶I和II的联合抑制已被证明可抑制多种依赖内质网蛋白质质量控制的病毒的复制。通过筛选一组脱氧野尻霉素和环糖醇糖模拟物，我们发现基于机制的ERα-葡萄糖苷酶II抑制剂1,6-环吡喃醇环硫酸盐能有效阻断肺上皮细胞中SARS-CoV-2的复制，阻止细胞内成熟刺突蛋白的产生，减少感染性子代的产生，并导致合胞体形成减少。通过基于活性的蛋白质谱分析，我们证实了在气液界面生长的原代气道上皮细胞中ERα-葡萄糖苷酶II受到抑制。1,6-环吡喃醇环硫酸盐可抑制早期大流行的以及最近的SARS-CoV-2变体，以及SARS-CoV和MERS-CoV。报道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靶向ERα-葡萄糖苷酶I和其他不参与内质网蛋白质质量控制的糖基加工酶。我们提出以共价和不可逆的方式选择性阻断内质网驻留的α-葡萄糖苷酶II作为寻找针对SARS-CoV-2和其他依赖内质网蛋白质质量控制的病毒的有效抗病毒药物的新策略。
