The pandemic of SARS-CoV-2 worldwide with successive emerging variants urgently calls for small-molecule oral drugs with broad-spectrum antiviral activity. Here, we show that carrimycin, a new macrolide antibiotic in the clinic and an antiviral candidate for SARS-CoV-2 in phase III trials, decreases the efficiency of programmed –1 ribosomal frameshifting of coronaviruses and thus impedes viral replication in a broad-spectrum fashion. Carrimycin binds directly to the coronaviral frameshift-stimulatory element (FSE) RNA pseudoknot, interrupting the viral protein translation switch from ORF1a to ORF1b and thereby reducing the level of the core components of the viral replication and transcription complexes. Combined carrimycin with known viral replicase inhibitors yielded a synergistic inhibitory effect on coronaviruses. Because the FSE mechanism is essential in all coronaviruses, carrimycin could be a new broad-spectrum antiviral drug for human coronaviruses by directly targeting the conserved coronaviral FSE RNA. This finding may open a new direction in antiviral drug discovery for coronavirus variants.

中文翻译：

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可利霉素通过直接结合病毒移码刺激元件的 RNA 假结，降低程序性 –1 核糖体移码的效率，从而抑制冠状病毒复制

SARS-CoV-2在全球范围内的流行以及不断出现的变种迫切需要具有广谱抗病毒活性的小分子口服药物。在这里，我们发现可利霉素（一种临床上的新型大环内酯类抗生素，也是 III 期试验中的 SARS-CoV-2 抗病毒候选药物）降低了冠状病毒程序性 –1 核糖体移码的效率，从而在广谱范围内阻碍病毒复制时尚。可利霉素直接与冠状病毒移码刺激元件 (FSE) RNA 假结结合，中断病毒蛋白从 ORF1a 到 ORF1b 的翻译转换，从而降低病毒复制和转录复合物核心成分的水平。可利霉素与已知的病毒复制酶抑制剂相结合，对冠状病毒产生协同抑制作用。由于FSE机制在所有冠状病毒中都是必不可少的，因此可利霉素可能通过直接靶向保守的冠状病毒FSE RNA而成为一种针对人类冠状病毒的新型广谱抗病毒药物。这一发现可能为冠状病毒变种的抗病毒药物发现开辟新方向。