We utilized a high-throughput cell-based assay to screen several
chemical libraries for inhibitors of herpes simplex virus 1 (HSV-1) gene expression. From this screen, four
aurora kinase inhibitors were identified that potently reduced gene expression during HSV-1 lytic
infection. HSV-1 is known to interact with cellular
kinases to regulate gene expression by modulating the phosphorylation and/or activities of viral and cellular
proteins. To date, the role of
aurora kinases in HSV-1 lytic
infection has not been reported. We demonstrated that three
aurora kinase inhibitors strongly reduced the transcript levels of immediate-early (IE) genes ICP0, ICP4, and ICP27 and impaired HSV-1
protein expression from all classes of HSV-1, including ICP0, ICP4, ICP8, and gC. These restrictions caused by the
aurora kinase inhibitors led to potent reductions in HSV-1 viral replication. The compounds TAK 901, JNJ 7706621, and
PF 03814735 decreased HSV-1 titers by 4,500-, 13,200-, and 8,400-fold, respectively, when present in a low micromolar range. The
antiviral activity of these compounds correlated with an apparent decrease in
histone H3 phosphorylation at
serine 10 (H3S10ph) during
viral infection, suggesting that the phosphorylation status of H3 influences HSV-1 gene expression. Furthermore, we demonstrated that the
aurora kinase inhibitors also impaired the replication of other
RNA and DNA viruses. These inhibitors significantly reduced yields of vaccinia virus (a poxvirus,
double-stranded DNA, cytoplasmic replication) and mouse hepatitis virus (a coronavirus, positive-sense single-strand
RNA [ssRNA]), whereas
vesicular stomatitis virus (rhabdovirus, negative-sense ssRNA) yields were unaffected. These results indicated that the activities of
aurora kinases play pivotal roles in the life cycles of diverse viruses. IMPORTANCE We have demonstrated that
aurora kinases play a role during HSV-1 lytic
infection. Three
aurora kinase inhibitors significantly impaired HSV-1 immediate-early gene expression. This led to a potent reduction in HSV-1
protein expression and viral replication. Together, our results illustrate a novel role for
aurora kinases in the HSV-1 lytic cycle and demonstrate that
aurora kinase inhibitors can restrict HSV-1 replication. Furthermore, these
aurora kinase inhibitors also reduced the replication of murine coronavirus and vaccinia virus, suggesting that multiple viral families utilize the
aurora kinases for their own replication.