Potential Antiviral Target for SARS-CoV-2:A Key Early Responsive Kinase during Viral Entry

Currently,there is no effective antiviral medication for coronavirus disease 2019(COVID-19)and the knowledge on the potential therapeutic target is in great need.Guided by a time-course transmission electron microscope(TEM)imaging,we analyzed early phosphorylation dynamics within the first 15 min during severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)viral entry.Based on alterations in the phosphorylation events,we found that kinase activities such as protein kinase C(PKC),interleukin-1 receptor-associated kinase 4(IRAK4),MAP/microtubule affinity-regulating kinase 3(MARK3),and TANK-binding kinase 1(TBK1)were affected within 15 min of infection.Application of the corresponding kinase inhibitors of PKC,IRAK4,and p38 showed significant inhibition of SARS-CoV-2 replication.Additionally,proinflammatory cytokine production was reduced by applying PKC and p38 inhibitors.By an acquisition of a combined image data using positiveand negative-sense RNA probes,as well as pseudovirus entry assay,we demonstrated that PKC contributed to viral entry into the host cell,and therefore,could be a potential COVID-19 therapeutic target.