Targeting the Coronavirus Nucleocapsid Protein through GSK-3 Inhibition

Xiaolei Liu; Anurag Verma; Holly Ramage; Gustavo Garcia; Rebecca L Myers; Anastasia Lucas; Jacob 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

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Targeting the Coronavirus Nucleocapsid Protein through GSK-3 Inhibition

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Targeting the Coronavirus Nucleocapsid Protein through GSK-3 Inhibition

Xiaolei Liu, Anurag Verma, Holly Ramage, Gustavo Garcia, Rebecca L Myers, Anastasia Lucas, Jacob J Michaelson, William Coryell, Arvind Kumar, Alexander Charney, …

medRxiv : the preprint server for health sciences

Cold Spring Harbor Laboratory

02/22/2021

DOI: 10.1101/2021.02.17.21251933

PMID: 33655282

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https://doi.org/10.1101/2021.02.17.21251933View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

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, 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 (odds ratio = 0.51 [0.34 - 0.76], p = 0.001). 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.

Details

Title: Subtitle: Targeting the Coronavirus Nucleocapsid Protein through GSK-3 Inhibition
Creators: Xiaolei Liu
Anurag Verma
Holly Ramage
Gustavo Garcia
Rebecca L Myers
Anastasia Lucas
Jacob J Michaelson - University of Iowa, Roy J. Carver Department of Biomedical Engineering
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
Resource Type: Preprint
Publication Details: medRxiv : the preprint server for health sciences
DOI: 10.1101/2021.02.17.21251933
PMID: 33655282
Publisher: Cold Spring Harbor Laboratory
Language: English
Date posted: 02/22/2021
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Communication Sciences and Disorders; Psychiatry; Iowa Neuroscience Institute
Record Identifier: 9984071700402771

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