Carrimycin inhibits coronavirus replication by decreasing the efficiency of programmed –1 ribosomal frameshifting through directly binding to the RNA pseudoknot of viral frameshift-stimulatory element
Hongying Li, Jianrui Li, Jiayu Li, Hu Li, Xuekai Wang, Jing Jiang, Jing Jiang, Lei Lei, Han Sun, Mei Tang, Biao Dong, Weiqing He, Shuyi Si, Bin Hong, Yinghong Li, Danqing Song, Zong‐Gen Peng, Yongsheng Che, Jian-Dong Jiang, Jian-Dong Jiang
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.