Editors' ChoiceVirology

New connections: Kinase inhibitors as antivirals

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Science Signaling  02 Oct 2018:
Vol. 11, Issue 550, eaau2211
DOI: 10.1126/scisignal.aau2211

Proteomics approaches identify diverse host kinases as potential antiviral therapeutic targets.

Viral infection profoundly alters cells, arresting mRNA translation and altering metabolism. To better understand the pathways involved, Yángüez et al. analyzed human lung epithelial cells after influenza virus (IAV) infection and found that substantial changes in phosphoprotein abundance occurred within minutes of infection. Gene ontology analysis and computational kinase prediction suggested IAV infection activated mitogen-activated protein kinase (MAPK) pathways and actin rearrangement, which have well-described roles in promoting viral infection. The authors further identified that IAV infection also activated other kinases, such as cyclin-dependent kinase1 (CDK1), CDK5, polo-like kinase 2 (PLK2), unc-51–like kinase 3 (ULK3), and G protein–coupled receptor kinase 2 (GRK2). Inhibitor studies confirmed that the activity of GRK2 was required for productive IAV infection. However, even at high concentrations, GRK2 inhibitors were only effective when cells were either pretreated or treated concurrently with infection, suggesting that GRK2 may be required for an early step in infection. Loss of GRK2 reduced the replication of distinct IAV isolates in multiple cell lines and human airway epithelial cell cultures. Treatment of mice with the antidepressant and GRK2 inhibitor Paroxetine reduced viral titers in the lungs of infected mice but did not protect them from lethal IAV challenge. Thus, inhibiting this GPCR-associated kinase with a widely available therapeutic may represent a new approach to reducing disease burden in IAV-susceptible populations, such as the elderly.

Another study from Ye et al. in the Science Signaling Archives used phosphoproteomics and kinase prediction to find that Japanese encephalitis virus (JEV) infection activates protein kinase A (PKA), the kinase AKT1, p53, and c-Jun N-terminal kinase 1(JNK1). Inhibition or loss of JNK1 reduced inflammatory cytokine production and matrix metalloprotease (MMP) abundance in infected cells. In mice, the JNK1 inhibitor reduced established viral infection and inflammatory cytokine abundance in the brain, which protected the mice from lethal disease. Together, these studies highlight the multiple unexpected ways that viruses use host cell kinases during infection and suggest that repurposing kinase inhibitors as therapies may be effective for a wide array of viral diseases with unmet need.

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