BX-795 inhibits HSV-1 and HSV-2 replication by blocking the JNK/p38 pathways without interfering with PDK1 activity in host cells.
BX-795 inhibits HSV-1 and HSV-2 replication by blocking the JNK/p38 pathways without interfering with PDK1 activity in host cells.
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DOI：
10.1038/aps.2016.160
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发表时间：
2017-03
影响因子：
8.2
通讯作者：
Wu ZW
中科院分区：
文献类型：
--
作者：
Su AR;Qiu M;Li YL;Xu WT;Song SW;Wang XH;Song HY;Zheng N;Wu ZW
BX-795是3-磷酸肌醇依赖性激酶1（PDK 1）的抑制剂，也是IKK相关激酶、TANK结合激酶1（TBK 1）和IKK β的强效抑制剂。在这项研究中，我们试图阐明BX-795抑制单纯疱疹病毒（HSV）复制的分子机制。用BX-795处理HEC-1-A或Vero细胞，并用HSV-1或HSV-2感染不同时期。BX-795（3.125 ~ 25 μmol/L）呈剂量依赖性抑制HSV-2的复制，对宿主细胞的毒性较低。BX-795处理剂量依赖性地抑制两个HSV立即早期（IE）基因（ICP 0和ICP 27）和晚期基因（gD）在感染后12小时的表达。HSV-2感染导致宿主细胞中PI 3 K和Akt的活化，BX-795处理抑制HSV-2诱导的Akt磷酸化和活化。然而，用LY 294002和雷帕霉素阻断PI 3 K/Akt/mTOR并不影响HSV-2的复制。HSV-2感染后8 h，宿主细胞中JNK和p38的磷酸化增加，ERK的磷酸化减少; BX-795处理抑制HSV-2诱导的JNK和p38 MAP激酶的激活以及JNK和p38 MAP激酶下游靶点c-Jun和ATF-2的磷酸化。此外，SB 203580（p38抑制剂）或SP 600125（JNK抑制剂）剂量依赖性地抑制宿主细胞中的病毒复制，而PD 98059（ERK抑制剂）无效。此外，BX-795阻断PMA刺激的c-Jun活化以及HSV-2介导的c-Jun核转位。BX-795剂量依赖性地抑制HSV-2、PMA、TNF-α诱导的AP-1活化，但不抑制HSV诱导的NF-κB活化。p38/JNK过表达减弱BX-795对HSV复制的抑制作用。BX-795完全阻断HSV-2诱导的MKK 4磷酸化，表明BX-795作用于JNK和p38 MAP激酶的上游。总之，本研究鉴定了BX-795的抗HSV活性及其对宿主细胞中JNK/p38 MAP激酶通路的靶向作用。
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 IKKɛ. 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.