Hu Ao, Li Jing, Tang Wei, Liu Ge, Zhang Haiwei, Liu Chunlan, Chen Xulin
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
University of Chinese Academy of Sciences, Beijing, China.
Front Microbiol. 2020 Feb 18;11:178. doi: 10.3389/fmicb.2020.00178. eCollection 2020.
Influenza virus RNA-dependent RNA polymerase (vRdRp) does not have capping activity and relies on the capped RNAs produced by the host RNA polymerase II (RNAPII). The viral polymerases process the capped RNAs to produce short capped RNA fragments that are used as primers to initiate the transcription of viral mRNAs. This process, known as cap-snatching, can be targeted by antiviral therapeutics. Here, anthralin was identified as an inhibitor against influenza a virus (IAV) infection by targeting the cap-snatching activity of the viral polymerase. Anthralin, an FDA-approved drug used in the treatment of psoriasis, shows antiviral activity against IAV infection and . Importantly, anthralin significantly reduces weight loss, lung injury, and mortality caused by IAV infection in mice. The mechanism of action study revealed that anthralin inhibits the cap-binding function of PB2 subunit and endonuclease activity of PA. As a result, viral mRNA transcription is blocked, leading to the decreases in viral RNA replication and viral protein expression. In conclusion, anthralin has been demonstrated to have the potential of an alternative antiviral against influenza virus infection. Also, targeting the captive pocket structure that includes the N-terminus of PA endonuclease domain and the C-terminal of PB2 cap-binding domain of IAV RdRp may be an excellent strategy for developing anti-influenza drugs.
流感病毒RNA依赖性RNA聚合酶（vRdRp）不具有加帽活性，依赖于宿主RNA聚合酶II（RNAPII）产生的带帽RNA。病毒聚合酶加工带帽RNA以产生短的带帽RNA片段，这些片段用作启动病毒mRNA转录的引物。这个过程称为帽抢夺，可被抗病毒治疗药物靶向。在这里，蒽林被确定为一种通过靶向病毒聚合酶的帽抢夺活性来抑制甲型流感病毒（IAV）感染的抑制剂。蒽林是一种经美国食品药品监督管理局（FDA）批准用于治疗银屑病的药物，对IAV感染具有抗病毒活性。重要的是，蒽林能显著减轻IAV感染小鼠的体重减轻、肺损伤和死亡率。作用机制研究表明，蒽林抑制PB2亚基的帽结合功能和PA的核酸内切酶活性。结果，病毒mRNA转录被阻断，导致病毒RNA复制和病毒蛋白表达减少。总之，蒽林已被证明具有作为抗流感病毒感染替代抗病毒药物的潜力。此外，靶向包括IAV RdRp的PA核酸内切酶结构域N端和PB2帽结合结构域C端的俘获口袋结构可能是开发抗流感药物的一个极佳策略。
