首页|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

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

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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 replica-tion 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 coro-naviruses.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.

CarrimycinCoronavirusBroad-spectrum antiviral activityProgrammed-1 ribosomal frameshiftingRNA pseudoknotAntiviral agentRNA targetSynergistic inhibitory effect

Hongying Li、Jianrui Li、Jiayu Li、Hu Li、Xuekai Wang、Jing Jiang、Lei Lei、Han Sun、Mei Tang、Biao Dong、Weiqing He、Shuyi Si、Bin Hong、Yinghong Li、Danqing Song、Zonggen Peng、Yongsheng Che、Jian-Dong Jiang

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CAMS Key Laboratory of Antiviral Drug Research,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences & Peking Union Medical College,Beijing 100050,China

Beijing Key Laboratory of Antimicrobial Agents,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences & Peking Union Medical College,Beijing 100050,China

Key Laboratory of Biotechnology of Antibiotics,the National Health and Family Planning Commission(NHFPC),Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences & Peking Union Medical College,Beijing 100050,China

Key Laboratory of Biotechnology of Antibiotics,the National Health and Family Planning Commission(NHFPC),Institute of Medicinal Biotechnology,Chinese Academy of Medical

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National Natural Science Foundation,ChinaNational key research and development program,ChinaCAMS Innovation Fund for Medical Sciences,ChinaCAMS Innovation Fund for Medical Sciences,ChinaCAMS Innovation Fund for Medical Sciences,China

821515252022YFC08690002022-I2M-JB-0132021-I2M-1-0282022-I2M-2-002

2024

10.1016/j.apsb.2024.02.023

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(6)
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