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首页> 美国卫生研究院文献>PLoS Clinical Trials >Baloxavir marboxil, a novel cap-dependent endonuclease inhibitor potently suppresses influenza virus replication and represents therapeutic effects in both immunocompetent and immunocompromised mouse models
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Baloxavir marboxil, a novel cap-dependent endonuclease inhibitor potently suppresses influenza virus replication and represents therapeutic effects in both immunocompetent and immunocompromised mouse models

机译：Baloxavir marboxil，一种新型的帽依赖性核酸内切酶抑制剂，可有效抑制流感病毒复制，并在具有免疫能力和免疫功能低下的小鼠模型中均具有治疗作用

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Baloxavir marboxil (BXM) is an orally available small molecule inhibitor of cap-dependent endonuclease (CEN), an essential enzyme in the initiation of mRNA synthesis of influenza viruses. In the present study, we evaluated the efficacy of BXM against influenza virus infection in mouse models. Single-day oral administration of BXM completely prevented mortality due to infection with influenza A and B virus in mice. Moreover, 5-day repeated administration of BXM was more effective for reducing mortality and body weight loss in mice infected with influenza A virus than oseltamivir phosphate (OSP), even when the treatment was delayed up to 96 hours post infection (p.i.). Notably, administration of BXM, starting at 72 hours p.i. led to significant decrease in virus titers of >2-log10 reduction compared to the vehicle control within 24 hours after administration. Virus reduction in the lung was significantly greater than that observed with OSP. In addition, profound and sustained reduction of virus titer was observed in the immunocompromised mouse model without emergence of variants possessing treatment-emergent amino acid substitutions in the target protein. In our immunocompetent and immunocompromised mouse models, delayed treatment with BXM resulted in rapid and potent reduction in infectious virus titer and prevention of signs of influenza infection, suggesting that BXM could extend the therapeutic window for patients with influenza virus infection regardless of the host immune status.
机译：Baloxavir marboxil（BXM）是可口服获得的帽依赖性核酸内切酶（CEN）的小分子抑制剂，CEN是启动流感病毒mRNA合成的必需酶。在本研究中，我们评估了BXM对小鼠模型中流感病毒感染的功效。每天口服BXM可以完全预防小鼠感染甲型和乙型流感病毒所致的死亡率。此外，即使将治疗推迟至感染后96小时（p.i.），重复5天的BXM给药也能比磷酸奥司他韦（OSP）更有效地降低感染甲型流感病毒的小鼠的死亡率和体重减轻。值得注意的是，从p.i. 72小时开始BXM的给药。与赋形剂对照相比，在给药后24小时内可导致病毒滴度显着降低> 2-log10。肺部的病毒减少明显大于OSP所观察到的。另外，在免疫受损的小鼠模型中观察到病毒效价的显着和持续降低，而在靶蛋白中没有出现具有治疗性氨基酸取代的变体。在我们的免疫能力强和免疫功能低下的小鼠模型中，BXM的延迟治疗导致传染性病毒效价快速有效降低并预防了流感感染的迹象，这表明BXM可以扩大流感病毒感染患者的治疗范围，而与宿主的免疫状态无关。

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