The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic poses an unprecedented challenge for health care and the global economy. Repurposing drugs that have shown promise in inhibiting other viral infections could allow for more rapid dispensation of urgently needed therapeutics. The Spike protein of SARS-CoV-2 is extensively glycosylated with 22 occupied N glycan sites and is required for viral entry. In other glycosylated viral proteins, glycosylation is required for interaction with calnexin and chaperone-mediated folding in the endoplasmic reticulum, and prevention of this interaction leads to unfolded viral proteins and thus inhibits viral replication. As such, we investigated two iminosugars, celgosivir, a prodrug of castanospermine, and UV-4, or N-(9-methoxynonyl)-1-deoxynojirimycin, a deoxynojirimycin derivative. Iminosugars are known inhibitors of the α-glucosidase I and II enzymes and were effective at inhibiting authentic SARS-CoV-2 viral replication in a cell culture system. Celgosivir prevented SARS-CoV-2-induced cell death and reduced viral replication and Spike protein levels in a dose-dependent manner in culture with Vero E6 cells. Castanospermine, the active form of celgosivir, was also able to inhibit SARS-CoV-2, confirming the canonical castanospermine mechanism of action of celgosivir. The monocyclic UV-4 also prevented SARS-CoV-2-induced death and reduced viral replication after 24 h of treatment, although the reduction in viral copies was lost after 48 h. Our findings suggest that iminosugars should be urgently investigated as potential SARS-CoV-2 inhibitors.

中文翻译：

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亚氨基糖 celgosivir、粟精胺和 UV-4 抑制 SARS-CoV-2 复制

严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 大流行给医疗保健和全球经济带来了前所未有的挑战。重新利用在抑制其他病毒感染方面显示出希望的药物，可以更快地分配急需的治疗药物。SARS-CoV-2 的 Spike 蛋白被 22 个占据的 N 聚糖位点广泛糖基化，是病毒进入所必需的。在其他糖基化病毒蛋白中，糖基化是与钙连接蛋白和伴侣介导的内质网折叠相互作用所必需的，阻止这种相互作用会导致病毒蛋白展开，从而抑制病毒复制。因此，我们研究了两种亚氨基糖，西戈西韦（一种粟精胺的前药）和 UV-4，或 N-（9-甲氧基壬基）-1-脱氧野尻霉素（一种脱氧野尻霉素衍生物）。亚氨基糖是已知的 α-葡萄糖苷酶 I 和 II 抑制剂，可有效抑制细胞培养系统中真正的 SARS-CoV-2 病毒复制。Celgosivir 在 Vero E6 细胞培养中以剂量依赖的方式阻止了 SARS-CoV-2 诱导的细胞死亡并降低了病毒复制和 Spike 蛋白水平。西戈西韦的活性形式栗精胺也能够抑制 SARS-CoV-2，证实了西戈西韦的经典栗精胺作用机制。单环 UV-4 还可以防止 SARS-CoV-2 诱导的死亡并在治疗 24 小时后减少病毒复制，尽管病毒拷贝的减少在 48 小时后消失了。我们的研究结果表明，亚氨基糖应作为潜在的 SARS-CoV-2 抑制剂进行紧急调查。