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：

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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。