We present a small molecule chemotype, identified by an orthogonal drug screen, exhibiting nanomolar activity against members of all the six viral families causing most human respiratory viral disease, with a demonstrated barrier to resistance development. Antiviral activity is shown in mammalian cells, including human primary bronchial epithelial cells cultured to an air-liquid interface and infected with SARS-CoV-2. In animals, efficacy of early compounds in the lead series is shown by survival (for a coronavirus) and viral load (for a paramyxovirus). The drug target is shown to include a subset of the protein 14-3-3 within a transient host multi-protein complex containing components implicated in viral lifecycles and in innate immunity. This multi-protein complex is modified upon viral infection and largely restored by drug treatment. Our findings suggest a new clinical therapeutic strategy for early treatment upon upper respiratory viral infection to prevent progression to lower respiratory tract or systemic disease.

中文翻译：

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针对宿主多蛋白复合物的泛呼吸道抗病毒化学型


我们提出了一种小分子化学型，通过正交药物筛选鉴定，对引起大多数人类呼吸道病毒疾病的所有六个病毒家族的成员表现出纳摩尔活性，并显示出对耐药性发展的障碍。哺乳动物细胞中显示出抗病毒活性，包括培养到气液界面并感染 SARS-CoV-2 的人原代支气管上皮细胞。在动物中，先导系列中早期化合物的功效通过存活率（对于冠状病毒）和病毒载量（对于副粘病毒）来显示。该药物靶标包括瞬时宿主多蛋白复合物中蛋白质 14-3-3 的一个子集，该复合物含有与病毒生命周期和先天免疫有关的成分。这种多蛋白复合物在病毒感染后发生修饰，并通过药物治疗很大程度上恢复。我们的研究结果提出了一种新的临床治疗策略，用于上呼吸道病毒感染的早期治疗，以防止进展为下呼吸道或全身性疾病。