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

Abstract

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 positive- and 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