PDF(Pubmed)
Abstract：
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.
摘要：
SARS-CoV-2在全球范围内流行，并相继出现变体，迫切需要具有广谱抗病毒活性的小分子口服药物。这里,我们展示了卡里霉素，临床上的一种新的大环内酯类抗生素和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化-1核糖体移码的效率，从而阻碍了病毒的广谱复制。携带霉素直接与冠状病毒移码刺激元件（FSE）RNA假结结合，中断从ORF1a到ORF1b的病毒蛋白翻译转换，从而降低病毒复制和转录复合物的核心成分的水平。将卡里霉素与已知的病毒复制酶抑制剂组合对冠状病毒产生协同抑制作用。因为FSE机制在所有冠状病毒中都是必不可少的，通过直接靶向保守的冠状病毒FSERNA，carrimycin可能是一种新型的人冠状病毒广谱抗病毒药物。这一发现可能为冠状病毒变体的抗病毒药物发现开辟新的方向。
