Inhibitors of One or More Cellular Aurora Kinases Impair the Replication of Herpes Simplex Virus 1 and Other DNA and RNA Viruses with Diverse Genomes and Life Cycles.
Inhibitors of One or More Cellular Aurora Kinases Impair the Replication of Herpes Simplex Virus 1 and Other DNA and RNA Viruses with Diverse Genomes and Life Cycles.
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DOI：
10.1128/spectrum.01943-22
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发表时间：
2023-02-14
影响因子：
3.7
通讯作者：
Davido, David J.
中科院分区：
文献类型：
--
作者：
Ly, Cindy Y.;Pfannenstiel, Jessica;Pant, Anil;Yang, Zhilong;Fehr, Anthony R.;Rodzkin, Maxim S.;Davido, David J.
我们利用高通量的细胞为基础的分析，以筛选几个化学库的抑制剂单纯疱疹病毒1（HSV-1）基因表达。从该筛选中，鉴定了四种极光激酶抑制剂，其在HSV-1裂解感染期间有效地降低基因表达。已知HSV-1与细胞激酶相互作用以通过调节病毒和细胞蛋白的磷酸化和/或活性来调节基因表达。迄今为止，极光激酶在HSV-1裂解性感染中的作用尚未报道。我们证明了三种极光激酶抑制剂强烈降低了即时早期（IE）基因ICP 0、ICP 4和ICP 27的转录水平，并损害了所有类型HSV-1（包括ICP 0、ICP 4、ICP 8和gC）的HSV-1蛋白表达。极光激酶抑制剂引起的这些限制导致HSV-1病毒复制的有效减少。当以低微摩尔浓度范围存在时，化合物TAK 901、JNJ 7706621和PF 03814735分别使HSV-1滴度降低4，500、13，200和8，400倍。这些化合物的抗病毒活性与病毒感染期间组蛋白H3丝氨酸10（H3 S10 ph）磷酸化的明显降低相关，表明H3的磷酸化状态影响HSV-1基因表达。此外，我们证明极光激酶抑制剂也损害了其他RNA和DNA病毒的复制。这些抑制剂显著降低了牛痘病毒（痘病毒，双链DNA，胞质复制）和小鼠肝炎病毒（冠状病毒，正义单链RNA [ssRNA]）的产量，而水泡性口炎病毒（弹状病毒，负义ssRNA）的产量不受影响。这些结果表明极光激酶的活性在不同病毒的生活史中起着关键作用。我们已经证明极光激酶在HSV-1裂解性感染过程中发挥作用。三种极光激酶抑制剂显着损害HSV-1立即早期基因表达。这导致HSV-1蛋白表达和病毒复制的有效减少。总之，我们的研究结果说明了极光激酶在HSV-1裂解周期中的新作用，并证明极光激酶抑制剂可以限制HSV-1复制。此外，这些极光激酶抑制剂还减少了鼠冠状病毒和牛痘病毒的复制，表明多个病毒家族利用极光激酶进行自身复制。
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.
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DOI：
10.1073/pnas.200375297
发表时间：
2000-09-26
影响因子：
11.1
作者：
Advani, SJ;Weichselbaum, RR;Roizman, B
通讯作者：
Roizman, B
影响因子：
3.7
作者：
Bonjardim, Claudio A.
通讯作者：
Bonjardim, Claudio A.
影响因子：
5.4
作者：
Liou, LY;Herrmann, CH;Rice, AP
通讯作者：
Rice, AP
影响因子：
4.4
作者：
Bell, Christina;Desjardins, Michel;Radtke, Kerstin
通讯作者：
Radtke, Kerstin
影响因子：
--
作者：
Duong-Ly, Krisna C;Peterson, Jeffrey R
通讯作者：
Peterson, Jeffrey R