Antiviral Effect Of BX795 Against Herpes Simplex Virus

BX795, an aminopyrimidine compound, was developed as an inhibitor of 3-phosphoinositide-dependent kinase 1 (PDK1) and later shown to be a potent inhibitor of the IKK-related kinase, TANK-binding kinase 1 (TBK1) and IKKε. In this study, we found that BX795 inhibited HSV-1 and HSV-2 replication through suppression of viral IE and late gene expression during viral infection, but not HSV IE gene transcription during early period of viral life cycle. Although BX795 was a potent PDK1 inhibitor and able to interfere with the HSV-2-induced activation of PI3K/Akt/mTOR, BX795 inhibition of HSV replication does not seem to be mediated by PDK1 pathway since the inhibition of PI3K/Akt/mTOR by other potent specific inhibitors, such as LY294002 and rapamycin, did not impede HSV-2 replication. BX795 also showed no inhibitory activity against HSV-induced NF-κB activity, a major stress signaling pathway that is an essential part of HSV replication. We found that BX795 potently inhibited HSV-mediated activation of cellular JNK and p38 MAP kinase pathways, which are known to be critical for the viral replication. Further studies showed that BX795 could also inhibit PMA-, TNF-α-induced MAPK and AP-1 activation. HSV ICPO-mediated AP-1 activation but not ICPO-mediated NF-κB activation was blocked by BX795. In conclusion, BX795 inhibited HSV viral infection in a JNK/p38-dependent manner, but may not be through its anti-PDK1 activity.