Abstract
We previously reported that carrimycin could inhibit pan-coronavirus including HCoV-229E, HCoV-OC43 and SARS-CoV-2. We found that carrimycin targeted the post-entry replicative events in coronavirus infection. Carrimycin could impede the viral protein translation switch from ORF1a to ORF1b by targeting programmed -1 ribosomal frameshifting (-1PRF). Carrimycin could also inhibit the newly synthesized (nascent) viral RNA. In this study we investigated whether carrimycin also inhibited the newly emerged SARS-CoV-2 variants. We showed that carrimycin (1.25–10 µM) dose-dependently inhibited both viral RNA and protein levels in Vero E6 cells. We further demonstrated that carrimycin disrupted the formation of SARS-CoV-2 double membrane vesicles (DMVs), and identified the host transmembrane protein B (TMEM41B) as the key factor involved in this process. Overexpression of TMEM41B increased viral protein levels and mRNA levels, whereas TMEM41B knockdown reduced viral replication including HCoV-229E, HCoV-OC43 and SARS-CoV-2. Moreover, overexpression of TMEM41B partially reversed the inhibitory effect of carrimycin, suggesting that carrimycin indeed exerted antiviral effects through regulation of TMEM41B. We revealed that carrimycin directly bound to TMEM41B and induced its K48 ubiquitination degradation, thereby inhibiting viral replication. These results expand the understanding of carrimycin’s antiviral mechanisms, particularly its antiviral activity, and enrich our knowledge about the role of host factors in regulating viral replication.
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Acknowledgements
We gratefully acknowledge Dr. Jing-dong Song (National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention) for technical supports and advice on the Transmission microscopy analysis. This work was financially supported by National Natural Science Foundation of China (82151525, 82003818, 82394464) and CAMS Innovation Fund for Medical Sciences (2021-I2M-1-030, 2022-I2M-CoV19-001), China.
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YHL, HQW and KW designed the experiments. YHL and JDJ directed the study. KW, HQW, GY, SW, HYY and MYW contributed to executing the described experiments. KW and HQW were responsible for the analysis of the data and preparation the manuscript. All authors approved the final version of the manuscript.
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Wang, K., Wang, Hq., Yang, G. et al. Carrimycin exhibited broad spectrum inhibitory activities against coronaviruses replication through down-regulating host factor TMEM41B. Acta Pharmacol Sin 46, 2006–2015 (2025). https://doi.org/10.1038/s41401-025-01577-9
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DOI: https://doi.org/10.1038/s41401-025-01577-9
