To probe SARS-CoV-2 dependence on MAPK signaling, SARS-CoV-2 replication was measured in response to pharmacological and genetic perturbation of MAPK components that were upregulated during infection (Figure 7D). Potent antiviral activity was observed for gilteritinib (Figure 7E; IC50 = 0.807 μM), an inhibitor of AXL kinase, upstream of p38; ralimetinib (Figure 7F; IC50 = 0.873 μM), an inhibitor of MAPK11 (p38ɑ) and MAPK14 (p38β); MAPK13-IN-1 (Figure 7G; IC50 = 4.63 μM), an inhibitor of MAPK13 (p38-δ); and ARRY-797 (Figure 7H; IC50 = 0.913 μM) in A549-ACE2 cells, a MAPK14 inhibitor. To further probe the dependence of SARS-CoV-2 on p38 pathway members, small interfering RNA (siRNA)-mediated knockdown of MAP2K3, p38-δ (MAPK13), and p38-ɣ (MAPK12) was performed in A549-ACE2 cells, and a significant decrease in SARS-CoV-2 replication was observed for all three, with little to no effect on cell viability (Figure 7I).