Identification and in vivo Efficacy Assessment of Approved Orally Bioavailable Human Host Protein-Targeting Drugs With Broad Anti-influenza A Activity
Identification and in vivo Efficacy Assessment of Approved Orally Bioavailable Human Host Protein-Targeting Drugs With Broad Anti-influenza A Activity
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DOI：
10.3389/fimmu.2019.01097
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发表时间：
2019-06-05
影响因子：
7.3
通讯作者：
von Messling, Veronika
中科院分区：
文献类型：
--
作者：
Enkirch, Theresa;Sauber, Svenja;von Messling, Veronika
甲型流感病毒的高度遗传变异性对季节性和大流行疫苗的开发构成了持续的挑战，使抗病毒药物成为抵御抗原性不同毒株或新亚型的第一道防线。随着针对病毒蛋白的药物的耐药性迅速出现，我们评估了已经批准的针对参与病毒生命周期的细胞蛋白的药物的抗病毒活性，这些药物是口服生物可利用的。在15种候选化合物中，有4种能够在体外抑制感染10至100倍而不产生毒性。其中两种药物，右美沙芬和酮替芬，在5到50 μ M之间显示出50%的有效剂量，不仅对经典的H1N1 PR8菌株，而且对大流行性H1N1和季节性H3N2菌株也有效。对小鼠的疗效评估显示，右美沙芬持续导致病毒肺滴度显著降低，同时也增强了奥司他韦的疗效。右美沙芬治疗感染大流行性H1N1毒株的雪貂可降低临床疾病严重程度，但未观察到对病毒滴度的影响。除了确定右美沙芬是一种潜在的流感治疗选择外，我们的研究还说明了生物信息学驱动的合理方法在重新利用已批准的抗传染病药物方面的可行性。
The high genetic variability of influenza A viruses poses a continual challenge to seasonal and pandemic vaccine development, leaving antiviral drugs as the first line of defense against antigenically different strains or new subtypes. As resistance against drugs targeting viral proteins emerges rapidly, we assessed the antiviral activity of already approved drugs that target cellular proteins involved in the viral life cycle and were orally bioavailable. Out of 15 candidate compounds, four were able to inhibit infection by 10- to 100-fold without causing toxicity, in vitro. Two of the drugs, dextromethorphan and ketotifen, displayed a 50% effective dose between 5 and 50 mu M, not only for the classic H1N1 PR8 strain, but also for a pandemic H1N1 and a seasonal H3N2 strain. Efficacy assessment in mice revealed that dextromethorphan consistently resulted in a significant reduction of viral lung titers and also enhanced the efficacy of oseltamivir. Dextromethorphan treatment of ferrets infected with a pandemic H1N1 strain led to a reduction in clinical disease severity, but no effect on viral titer was observed. In addition to identifying dextromethorphan as a potential influenza treatment option, our study illustrates the feasibility of a bioinformatics-driven rational approach for repurposing approved drugs against infectious diseases.