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

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

bioRxiv : the preprint server for biology (2020-08-21)
Tomer M Yaron, Brook E Heaton, Tyler M Levy, Jared L Johnson, Tristan X Jordan, Benjamin M Cohen, Alexander Kerelsky, Ting-Yu Lin, Katarina M Liberatore, Danielle K Bulaon, Edward R Kastenhuber, Marisa N Mercadante, Kripa Shobana-Ganesh, Long He, Robert E Schwartz, Shuibing Chen, Harel Weinstein, Oliver Elemento, Elena Piskounova, Benjamin E Nilsson-Payant, Gina Lee, Joseph D Trimarco, Kaitlyn N Burke, Cait E Hamele, Ryan R Chaparian, Alfred T Harding, Aleksandra Tata, Xinyu Zhu, Purushothama Rao Tata, Clare M Smith, Anthony P Possemato, Sasha L Tkachev, Peter V Hornbeck, Sean A Beausoleil, Shankara K Anand, François Aguet, Gad Getz, Andrew D Davidson, Kate Heesom, Maia Kavanagh-Williamson, David Matthews, Benjamin R tenOever, Lewis C Cantley, John Blenis, Nicholas S Heaton
ABSTRACT

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.

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Sigma-Aldrich
Anti-dsRNA Antibody, clone rJ2, culture supernatant, clone rJ2, from mouse