2. Academic Validation
  3. 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. 2020 Dec 16:2020.08.14.251207. doi: 10.1101/2020.08.14.251207.
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
PMID: 32817937 DOI: 10.1101/2020.08.14.251207
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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