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

Publication ,  Journal Article
Yaron, TM; Heaton, BE; Levy, TM; Johnson, JL; Jordan, TX; Cohen, BM; Kerelsky, A; Lin, T-Y; Liberatore, KM; Bulaon, DK; Kastenhuber, ER; He, L ...
Published in: bioRxiv
December 16, 2020

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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bioRxiv

DOI

Publication Date

December 16, 2020

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United States
 

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Yaron, T. M., Heaton, B. E., Levy, T. M., Johnson, J. L., Jordan, T. X., Cohen, B. M., … Heaton, N. S. (2020). The FDA-approved drug Alectinib compromises SARS-CoV-2 nucleocapsid phosphorylation and inhibits viral infection in vitro. BioRxiv. https://doi.org/10.1101/2020.08.14.251207
Yaron, Tomer M., Brook E. Heaton, Tyler M. Levy, Jared L. Johnson, Tristan X. Jordan, Benjamin M. Cohen, Alexander Kerelsky, et al. “The FDA-approved drug Alectinib compromises SARS-CoV-2 nucleocapsid phosphorylation and inhibits viral infection in vitro.BioRxiv, December 16, 2020. https://doi.org/10.1101/2020.08.14.251207.
Yaron TM, Heaton BE, Levy TM, Johnson JL, Jordan TX, Cohen BM, et al. The FDA-approved drug Alectinib compromises SARS-CoV-2 nucleocapsid phosphorylation and inhibits viral infection in vitro. bioRxiv. 2020 Dec 16;
Yaron, Tomer M., et al. “The FDA-approved drug Alectinib compromises SARS-CoV-2 nucleocapsid phosphorylation and inhibits viral infection in vitro.BioRxiv, Dec. 2020. Pubmed, doi:10.1101/2020.08.14.251207.
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. The FDA-approved drug Alectinib compromises SARS-CoV-2 nucleocapsid phosphorylation and inhibits viral infection in vitro. bioRxiv. 2020 Dec 16;

Published In

bioRxiv

DOI

Publication Date

December 16, 2020

Location

United States