The FDA-approved drug Alectinib compromises SARS-CoV-2 nucleocapsid phosphorylation and inhibits viral infection in vitro PMID: 32817937

Target-related Cytokines

2026-09-23

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

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.