BX-795 inhibits HSV-1 and HSV-2 replication by blocking the JNK/p38 pathways without interfering with PDK1 activity in host cells

Abstract

BX-795 is an inhibitor of 3-phosphoinositide-dependent kinase 1 (PDK1), but also a potent inhibitor of the IKK-related kinase, TANKbinding kinase 1 (TBK1) and IKKε. In this study we attempted to elucidate the molecular mechanism(s) underlying the inhibition of BX-795 on Herpes simplex virus (HSV) replication. HEC-1-A or Vero cells were treated with BX-795 and infected with HSV-1 or HSV-2 for different periods. BX-795 (3.125-25 µmol/L) dose-dependently suppressed HSV-2 replication, and displayed a low cytotoxicity to the host cells. BX-795 treatment dose-dependently suppressed the expression of two HSV immediate-early (IE) genes (ICP0 and ICP27) and the late gene (gD) at 12 h postinfection. HSV-2 infection resulted in the activation of PI3K and Akt in the host cells, and BX-795 treatment inhibited HSV-2-induced Akt phosphorylation and activation. However, the blockage of PI3K/Akt/mTOR with LY294002 and rapamycin did not affect HSV-2 replication. HSV-2 infection increased the phosphorylation of JNK and p38, and reduced ERK phosphorylation at 8 h postinfection in the host cells; BX-795 treatment inhibited HSV-2-induced activation of JNK and p38 MAP kinase as well as the phosphorylation of c-Jun and ATF-2, the downstream targets of JNK and p38 MAP kinase. Furthermore, SB203580 (a p38 inhibitor) or SP600125 (a JNK inhibitor) dose-dependently inhibited the viral replication in the host cells, whereas PD98059 (an ERK inhibitor) was not effective. Moreover, BX-795 blocked PMA-stimulated c-Jun activation as well as HSV-2-mediated c-Jun nuclear translocation. BX-795 dose-dependently inhibited HSV-2, PMA, TNF-α-stimulated AP-1 activation, but not HSV-induced NF-κB activation. Overexpression of p38/JNK attenuated the inhibitory effect of BX-795 on HSV replication. BX-795 completely blocked HSV-2-induced MKK4 phosphorylation, suggesting that BX-795 acting upstream of JNK and p38 MAP kinase. In conclusion, this study identifies the anti-HSV activity of BX-795 and its targeting of the JNK/p38 MAP kinase pathways in host cells.

Antiviral effect of Chinese herbal prescription JieZe-1 on adhesion and penetration of VK2/E6E7 with herpes simplex viruses type 2

“…Firstly, we explored the anti-HSV-2 effects of JZ-1, penciclovir and berberine at 6 h, 12 h, 18 h, and 24 h of treatment. Immunofluorescence microscopy analysis of gD expression showed that only JZ-1 had an antiviral effect at the treatment of 6 h. Since the late gene transcription products of HSV-2, including gB, gC, gD, gE, gG, and other viral structural proteins, are produced significantly 12-15 h after infection (Ibáñez et al, 2018;Su et al, 2017), the gD observed in host cells at 6 h of infection was mostly derived from the original virons that infected the cells, suggesting that JZ-1 plays a vital role in the early Fig. 5.…”

Coupled immune stratification and identification of therapeutic candidates in patients with lung adenocarcinoma

“…Another concern is BX-795, a known multi-target kinase inhibitor [ 45 , 46 ]. Researches in recent years found that it exhibited inhibitory activity against virus infection and various cancer [ 47 – 49 ]. In this work, we found that BX795 can inhibit IKBKE and KDR at the same time correct aberrant gene expression in the C3 subgroup.…”

A new advanced in silico drug discovery method for novel coronavirus (SARS-CoV-2) with tensor decomposition-based unsupervised feature extraction

“…BX-795 has the 11th smallest (significant) P-value in "LINCS L1000 Chem Pert up" and had multiple hits (S8 Table). BX-795 inhibits HSV-1 and HSV-2 replication by blocking the JNK/p38 pathways without interfering with PDK1 activity in host cells [13]. Su et al [13] also suggested SARS-CoV as a target of BX-795.…”