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Multiple coronaviruses have emerged independently in the past 20 years that cause lethal human diseases. Although vaccine development targeting these viruses has been accelerated substantially, there remain patients requiring treatment who cannot be vaccinated or who experience breakthrough infections. Understanding the common host factors necessary for the life cycles of coronaviruses may reveal conserved therapeutic targets. Here, we used the known substrate specificities of mammalian protein kinases to deconvolute the sequence of phosphorylation events mediated by three host protein kinase families (SRPK, GSK-3, and CK1) that coordinately phosphorylate a cluster of serine and threonine residues in the viral N protein, which is required for viral replication. We also showed that loss or inhibition of SRPK1/2, which we propose initiates the N protein phosphorylation cascade, compromised the viral replication cycle. Because these phosphorylation sites are highly conserved across coronaviruses, inhibitors of these protein kinases not only may have therapeutic potential against COVID-19 but also may be broadly useful against coronavirus-mediated diseases. Targeting the host instead of the virus: Although vaccines have been very effective in responding to the COVID-19 pandemic caused by the virus SARS-CoV-2, there is a continuing need to develop new therapeutics. Through phosphoproteomic analysis of SARS-CoV-2–infected cells, Yaron et al. identified multiple phosphorylation sites in a conserved region of the viral nucleocapsid (N) protein, which is critical for viral replication. Biochemical analyses identified the host kinases that sequentially phosphorylated distinct motifs in the N protein, and knockdown or inhibition of members of the priming kinase family SPRK reduced N protein phosphorylation. An FDA-approved drug that can inhibit kinases of the SRPK family reduced N protein phosphorylation and blocked viral replication in vitro, suggesting that the approach of targeting host proteins required by the virus might have therapeutic potential in the treatment of coronavirus-mediated infections. [ABSTRACT FROM AUTHOR]