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...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.展开更多
COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development.No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infection...COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development.No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections.We report herein that a macrolide antibiotic,carrimycin,potently inhibited the cytopathic effects(CPE)and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229 E,OC43,and SARS-CoV-2.Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection.In support of this notion,metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA.Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.展开更多
基金supported by grants from the National Natural Science Foundation,China(82151525)the National key research and development program,China(2022YFC0869000)the CAMS Innovation Fund for Medical Sciences(2022-I2M-JB-013,2021-I2M-1-028 and 2022-I2M-2-002,China).
文摘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.
基金financially supported by CAMS Initiative for Innovative Medicine(2020-I2M-Co V19-008,China)the National Science and Technology Major Projects for“Major New Drugs Innovation and Development”(2018ZX09711003,China)+1 种基金the National Key Research and Development Program of China(2020YFC0844900,China)Fundamental Research Funds for CAMS of China(2020HY320001,China)
文摘COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development.No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections.We report herein that a macrolide antibiotic,carrimycin,potently inhibited the cytopathic effects(CPE)and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229 E,OC43,and SARS-CoV-2.Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection.In support of this notion,metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA.Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.
