Yang Xuanye, Feng Xili, Liu Qianyun, An Lele, Ma Zhongren, Ma Xiaoxia
Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China.
College of Life Science and Engineering, Northwest Minzu University, Lanzhou, China.
Front Microbiol. 2025 Jun 5;16:1600935. doi: 10.3389/fmicb.2025.1600935. eCollection 2025.
Influenza epidemics represent a significant threat to global public health, primarily caused by the influenza viruses A and B. Although antiviral drugs targeting the influenza virus, such as zanamivir and oseltamivir, are clinically available, the emergence of virus evolution and drug resistance necessitates the development of host-directed therapies. Protein kinases are essential components of host signaling pathways, including the orchestration of virus-host interactions. By screening a library of kinase inhibitors, we identified that OTS167, a pharmacological inhibitor of maternal embryonic leucine zipper kinase (MELK), strongly inhibits the infections caused by multiple influenza virus subtypes in cell culture. This antiviral activity was further confirmed by treatment with another MELK pharmacological inhibitor, MELK-8a, and siRNA-mediated MELK gene silencing. In mice challenged with the influenza A virus, treatment with OTS167 inhibited both viral replication and lung inflammation. Mechanistically, inhibition of MELK by OTS167 downregulates the downstream effector CDK1, thereby inhibiting influenza virus M1 mRNA splicing to reduce viral replication and virus particle assembly. Finally, we demonstrated that combining OTS167 with zanamivir or oseltamivir resulted in additive antiviral activity. In conclusion, we identified MELK as a crucial host kinase that supports the influenza virus infection. OTS167, a pharmacological inhibitor of MELK currently undergoing phase II clinical trials for treating cancer, potently inhibits influenza virus infections and in mice, representing a promising lead for developing novel influenza antivirals.
流感流行对全球公共卫生构成重大威胁，主要由甲型和乙型流感病毒引起。尽管临床上已有针对流感病毒的抗病毒药物，如扎那米韦和奥司他韦，但病毒进化和耐药性的出现使得开发宿主导向疗法成为必要。蛋白激酶是宿主信号通路的重要组成部分，包括协调病毒与宿主的相互作用。通过筛选激酶抑制剂文库，我们发现母体胚胎亮氨酸拉链激酶（MELK）的药理抑制剂OTS167在细胞培养中能强烈抑制多种流感病毒亚型引起的感染。另一种MELK药理抑制剂MELK-8a以及siRNA介导的MELK基因沉默处理进一步证实了这种抗病毒活性。在用甲型流感病毒攻击的小鼠中，OTS167治疗可抑制病毒复制和肺部炎症。从机制上讲，OTS167对MELK的抑制作用下调了下游效应物CDK1，从而抑制流感病毒M1 mRNA剪接，减少病毒复制和病毒颗粒组装。最后，我们证明将OTS167与扎那米韦或奥司他韦联合使用可产生相加的抗病毒活性。总之，我们确定MELK是支持流感病毒感染的关键宿主激酶。OTS167是一种目前正在进行治疗癌症的II期临床试验的MELK药理抑制剂，在小鼠中能有效抑制流感病毒感染，是开发新型流感抗病毒药物的一个有前景的先导物。
