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SARS-CoV-2 proteins

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    Targeting the Coronavirus Nucleocapsid Protein PROTEIN through GSK-3 Inhibition

    Authors: Xiaolei Liu; Anurag Verma; Holly Ramage; Gustavo Garcia; Rebecca L Myers; Anastasia Lucas; Jake J Michaelson; William Coryell; Arvind Kumar; Alexander Charney; Marcelo G. Kazanietz; Daniel J. Rader; Marylyn D. Ritchie; Wade H. Berrettini; Robert Damoiseaux; Vaithilingaraja Arumugaswami; David Schultz; Sara Cherry; Peter S. Klein

    doi:10.1101/2021.02.17.21251933 Date: 2021-02-22 Source: medRxiv

    The coronaviruses responsible for severe acute respiratory syndrome MESHD ( SARS-CoV MESHD), COVID-19 MESHD (SARS-CoV-2), Middle East respiratory syndrome MESHD ( MERS-CoV MESHD), and other coronavirus infections MESHD express a nucleocapsid protein (N PROTEIN) that is essential for viral replication, transcription, and virion assembly. Phosphorylation of N from SARS-CoV MESHD 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 PROTEIN contains GSK-3 consensus sequences and that this motif is conserved in diverse coronaviruses, despite limited overall sequence conservation, 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 MESHD (odds ratio = 0.51 [0.34 - 0.76], p = 0.001). We also show that the SARS-CoV-2 N protein PROTEIN is phosphorylated by GSK-3. Knockout of GSK3A HGNC and GSK3B HGNC demonstrates that GSK-3 is essential for N phosphorylation. Alternative GSK-3 inhibitors block N phosphorylation and impair replication in SARS-CoV-2 infected MESHD lung epithelial cells in a cell-type dependent manner. Targeting GSK-3 may therefore provide a new approach to treat COVID-19 MESHD and future coronavirus outbreaks.

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MeSH Disease
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SARS-CoV-2 Proteins


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