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Inhibition of Human Adenovirus Replication by the Importin α/β1 Nuclear Import Inhibitor Ivermectin.
Journal of Virology ( IF 4.0 ) Pub Date : 2020-08-31 , DOI: 10.1128/jvi.00710-20
Cason R King 1 , Tanner M Tessier 1 , Mackenzie J Dodge 1 , Jason B Weinberg 2, 3 , Joe S Mymryk 4, 5, 6
Affiliation  

Human adenoviruses (HAdV) are ubiquitous within the human population and comprise a significant burden of respiratory illnesses worldwide. Pediatric and immunocompromised individuals are at particular risk for developing severe disease; however, no approved antiviral therapies specific to HAdV exist. Ivermectin is an FDA-approved broad-spectrum antiparasitic drug that also exhibits antiviral properties against a diverse range of viruses. Its proposed function is inhibiting the classical protein nuclear import pathway mediated by importin-α (Imp-α) and -β1 (Imp-β1). Many viruses, including HAdV, rely on this host pathway for transport of viral proteins across the nuclear envelope. In this study, we show that ivermectin inhibits HAdV-C5 early gene transcription, early and late protein expression, genome replication, and production of infectious viral progeny. Similarly, ivermectin inhibits genome replication of HAdV-B3, a clinically important pathogen responsible for numerous recent outbreaks. Mechanistically, we show that ivermectin disrupts binding of the viral E1A protein to Imp-α without affecting the interaction between Imp-α and Imp-β1. Our results further extend ivermectin’s broad antiviral activity and provide a mechanistic underpinning for its mode of action as an inhibitor of cellular Imp-α/β1-mediated nuclear import.

中文翻译:

Importinα/β1核输入抑制剂伊维菌素对人腺病毒复制的抑制作用。

人腺病毒(HAdV)在人群中无处不在,在全世界范围内构成重大的呼吸道疾病负担。小儿和免疫力低下的人特别容易患上严重的疾病;但是,不存在批准的针对HAdV的抗病毒疗法。伊维菌素是FDA批准的广谱抗寄生虫药,对多种病毒也具有抗病毒特性。其拟议的功能是抑制由importin-α(Imp-α)和-β1(Imp-β1)介导的经典蛋白质核输入途径。许多病毒,包括HAdV,都依赖此宿主途径在整个核膜中运输病毒蛋白。在这项研究中,我们显示伊维菌素可抑制HAdV-C5早期基因转录,早期和晚期蛋白质表达,基因组复制,和感染性病毒后代的生产。同样,伊维菌素抑制HAdV-B3的基因组复制,HAdV-B3是临床上重要的病原体,可导致许多近期爆发。从机理上讲,我们显示伊维菌素可破坏病毒E1A蛋白与Imp-α的结合,而不会影响Imp-α与Imp-β1之间的相互作用。我们的结果进一步扩展了伊维菌素的广泛抗病毒活性,并为其作为细胞Imp-α/β1介导的核输入抑制剂的作用方式提供了机制基础。
更新日期:2020-08-31
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