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

Overview

Journal Acta Pharm Sin B

Publisher Elsevier

Specialty Pharmacology

Date 2024 Jun 3

PMID 38828157

Authors

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

Affiliations

Soon will be listed here.

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.

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