Liu Xiaolei, Verma Anurag, Garcia Gustavo, Ramage Holly, Myers Rebecca L, Lucas Anastasia, Michaelson Jacob J, Coryell William, Kumar Arvind, Charney Alexander W, Kazanietz Marcelo G, Rader Daniel J, Ritchie Marylyn D, Berrettini Wade H, Schultz David C, Cherry Sara, Damoiseaux Robert, Arumugaswami Vaithilingaraja, Klein Peter S
medRxiv. 2021 Jul 21:2021.02.17.21251933. doi: 10.1101/2021.02.17.21251933.
The coronaviruses responsible for severe acute respiratory syndrome (SARS-CoV), COVID-19 (SARS-CoV-2), Middle East respiratory syndrome (MERS-CoV), and other coronavirus infections express a nucleocapsid protein (N) that is essential for viral replication, transcription, and virion assembly. Phosphorylation of N from SARS-CoV by glycogen synthase kinase 3 (GSK-3) is required for its function and inhibition of GSK-3 with lithium impairs N phosphorylation, viral transcription, and replication. Here we report that the SARS-CoV-2 N protein contains GSK-3 consensus sequences and that this motif is conserved in diverse coronaviruses, raising the possibility that SARS-CoV-2 may be sensitive to GSK-3 inhibitors including lithium. We conducted a retrospective analysis of lithium use in patients from three major health systems who were PCR tested for SARS-CoV-2. We found that patients taking lithium have a significantly reduced risk of COVID-19 (odds ratio = 0.51 [0.35 - 0.74], p = 0.005). We also show that the SARS-CoV-2 N protein is phosphorylated by GSK-3. Knockout of and demonstrates that GSK-3 is essential for N phosphorylation. Alternative GSK-3 inhibitors block N phosphorylation and impair replication in SARS-CoV-2 infected lung epithelial cells in a cell-type dependent manner. Targeting GSK-3 may therefore provide a new approach to treat COVID-19 and future coronavirus outbreaks.
COVID-19 is taking a major toll on personal health, healthcare systems, and the global economy. With three betacoronavirus epidemics in less than 20 years, there is an urgent need for therapies to combat new and existing coronavirus outbreaks. Our analysis of clinical data from over 300,000 patients in three major health systems demonstrates a 50% reduced risk of COVID-19 in patients taking lithium, a direct inhibitor of glycogen synthase kinase-3 (GSK-3). We further show that GSK-3 is essential for phosphorylation of the SARS-CoV-2 nucleocapsid protein and that GSK-3 inhibition blocks SARS-CoV-2 infection in human lung epithelial cells. These findings suggest an antiviral strategy for COVID-19 and new coronaviruses that may arise in the future.
导致严重急性呼吸综合征（SARS-CoV）、COVID-19（SARS-CoV-2）、中东呼吸综合征（MERS-CoV）以及其他冠状病毒感染的冠状病毒表达一种核衣壳蛋白（N），该蛋白对于病毒复制、转录和病毒体组装至关重要。糖原合酶激酶3（GSK-3）对SARS-CoV的N蛋白进行磷酸化是其功能所必需的，而用锂抑制GSK-3会损害N蛋白的磷酸化、病毒转录和复制。在此我们报告，SARS-CoV-2的N蛋白含有GSK-3共有序列，并且该基序在多种冠状病毒中保守，这增加了SARS-CoV-2可能对包括锂在内的GSK-3抑制剂敏感的可能性。我们对来自三个主要医疗系统的接受SARS-CoV-2 PCR检测的患者的锂使用情况进行了回顾性分析。我们发现服用锂的患者感染COVID-19的风险显著降低（优势比 = 0.51 [0.35 - 0.74]，p = 0.005）。我们还表明SARS-CoV-2的N蛋白被GSK-3磷酸化。敲除 和 证明GSK-3对于N蛋白的磷酸化至关重要。其他GSK-3抑制剂以细胞类型依赖的方式阻断N蛋白的磷酸化并损害SARS-CoV-2感染的肺上皮细胞中的复制。因此，靶向GSK-3可能为治疗COVID-19和未来的冠状病毒爆发提供一种新方法。
COVID-19正在对个人健康、医疗系统和全球经济造成重大损失。在不到20年的时间里出现了三次β冠状病毒疫情，迫切需要对抗新出现和现有的冠状病毒爆发的疗法。我们对来自三个主要医疗系统的超过300,000名患者的临床数据的分析表明，服用锂（糖原合酶激酶-3（GSK-3）的直接抑制剂）的患者感染COVID-19的风险降低了50%。我们进一步表明GSK-3对于SARS-CoV-2核衣壳蛋白的磷酸化至关重要，并且GSK-3抑制可阻断人肺上皮细胞中的SARS-CoV-2感染。这些发现提示了一种针对COVID-19和未来可能出现的新型冠状病毒的抗病毒策略。
