Open AccessTargeting the coronavirus nucleocapsid protein through GSK-3 inhibition
Author(s) -
Xiaolei Liu,
Anurag Verma,
Gustavo García,
Holly Ramage,
Anastasia Lucas,
Rebecca L. Myers,
Jacob J. Michaelson,
William Coryell,
Arvind Kumar,
Alexander Charney,
Marcelo G. Kazanietz,
Daniel J. Rader,
Marylyn D. Ritchie,
Wade H. Berrettini,
D. Schultz,
Sara Cherry,
Robert Damoiseaux,
Vaithilingaraja Arumugaswami,
Peter S. Klein
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2113401118
Subject(s) - coronavirus , gsk 3 , betacoronavirus , virology , outbreak , coronaviridae , covid-19 , gsk3b , phosphorylation , biology , medicine , biochemistry , disease , infectious disease (medical specialty)
The coronaviruses responsible for severe acute respiratory syndrome (SARS-CoV), COVID-19 (SARS-CoV-2), Middle East respiratory syndrome-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 GSK3A and GSK3B 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 an approach to treat COVID-19 and future coronavirus outbreaks.