The FDA-approved drug Alectinib compromises SARS-CoV-2 nucleocapsid phosphorylation and inhibits viral infection in vitro.

Journal Article

While vaccines are vital for preventing COVID-19 infections, it is critical to develop new therapies to treat patients who become infected. Pharmacological targeting of a host factor required for viral replication can suppress viral spread with a low probability of viral mutation leading to resistance. In particular, host kinases are highly druggable targets and a number of conserved coronavirus proteins, notably the nucleoprotein (N), require phosphorylation for full functionality. In order to understand how targeting kinases could be used to compromise viral replication, we used a combination of phosphoproteomics and bioinformatics as well as genetic and pharmacological kinase inhibition to define the enzymes important for SARS-CoV-2 N protein phosphorylation and viral replication. From these data, we propose a model whereby SRPK1/2 initiates phosphorylation of the N protein, which primes for further phosphorylation by GSK-3a/b and CK1 to achieve extensive phosphorylation of the N protein SR-rich domain. Importantly, we were able to leverage our data to identify an FDA-approved kinase inhibitor, Alectinib, that suppresses N phosphorylation by SRPK1/2 and limits SARS-CoV-2 replication. Together, these data suggest that repurposing or developing novel host-kinase directed therapies may be an efficacious strategy to prevent or treat COVID-19 and other coronavirus-mediated diseases.

Full Text

Duke Authors

Cited Authors

  • Yaron, TM; Heaton, BE; Levy, TM; Johnson, JL; Jordan, TX; Cohen, BM; Kerelsky, A; Lin, T-Y; Liberatore, KM; Bulaon, DK; Kastenhuber, ER; Mercadante, MN; Shobana-Ganesh, K; He, L; Schwartz, RE; Chen, S; Weinstein, H; Elemento, O; Piskounova, E; Nilsson-Payant, BE; Lee, G; Trimarco, JD; Burke, KN; Hamele, CE; Chaparian, RR; Harding, AT; Tata, A; Zhu, X; Tata, PR; Smith, CM; Possemato, AP; Tkachev, SL; Hornbeck, PV; Beausoleil, SA; Anand, SK; Aguet, F; Getz, G; Davidson, AD; Heesom, K; Kavanagh-Williamson, M; Matthews, D; tenOever, BR; Cantley, LC; Blenis, J; Heaton, NS

Published Date

  • December 16, 2020

Published In

  • Biorxiv

PubMed ID

  • 32817937

Pubmed Central ID

  • PMC7430567

Digital Object Identifier (DOI)

  • 10.1101/2020.08.14.251207

Language

  • eng

Conference Location

  • United States