Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus

Al-Beltagi, Sarah; Preda, Cristian Alexandru; Goulding, Leah V.; James, Joe; Pu, Juan; Skinner, Paul; Jiang, Min; Wang, Belinda Lei; Yang, Jiayun; Banyard, Ashley C.; Mellits, Kenneth H.; Gershkovich, Pavel; Hayes, Christopher J.; Nguyen-Van-Tam, Jonathan; Brown, Ian H.; Liu, Jinhua; Chang, Kin-Chow

Abstract

The long-term control strategy of SARS-CoV-2 and other major respiratory viruses needs to in-clude antivirals to treat acute infections, in addition to the judicious use of effective vaccines. Whilst COVID-19 vaccines are being rolled out for mass vaccination, the modest number of an-tivirals in use or development for any disease bears testament to the challenges of antiviral de-velopment. We recently showed that non-cytotoxic levels of thapsigargin (TG), an inhibitor of the sarcoplasmic / endoplasmic reticulum (ER) Ca2+ ATPase pump, induces a potent host innate immune antiviral response that blocks influenza A virus replication. Here we show that TG is also highly effective in blocking the replication of respiratory syncytial virus (RSV), common cold coronavirus OC43, SARS-CoV-2 and influenza A virus in immortalized or primary human cells. TG’s antiviral performance was significantly better than remdesivir and ribavirin in their respective inhibition of OC43 and RSV. Notably, TG was just as inhibitory to coronaviruses (OC43 and SARS-CoV-2) and influenza viruses (USSR H1N1 and pdm 2009 H1N1) in separate in-fections as in co-infections. Post-infection oral gavage of acid-stable TG protected mice against lethal influenza virus challenge. Together with its ability to inhibit the different viruses before or during active infection, and with an antiviral duration of at least 48 h post-TG exposure, we propose that TG (or its derivatives) is a promising broad-spectrum inhibitor against SARS-CoV-2, OC43, RSV and influenza virus.

Citation

Al-Beltagi, S., Preda, C. A., Goulding, L. V., James, J., Pu, J., Skinner, P., Jiang, M., Wang, B. L., Yang, J., Banyard, A. C., Mellits, K. H., Gershkovich, P., Hayes, C. J., Nguyen-Van-Tam, J., Brown, I. H., Liu, J., & Chang, K.-C. (2021). Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus. Viruses, 13(2), Article 234. https://doi.org/10.3390/v13020234

• Journal Article Type: Article
• Acceptance Date: Jan 26, 2021
• Online Publication Date: Feb 3, 2021
• Publication Date: Feb 1, 2021
• Deposit Date: Jan 26, 2021
• Publicly Available Date: Feb 1, 2021
• Journal: Viruses
• Electronic ISSN: 1999-4915
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 2
• Article Number: 234
• DOI: https://doi.org/10.3390/v13020234
• Keywords: thapsigargin; inhibitor; antiviral; SARS-CoV-2; coronavirus OC43; respiratory syncytial 44 virus; influenza virus; broad-spectrum; innate immunity; mouse; remdesivir; ribavirin; oseltamivir
• Public URL: https://nottingham-repository.worktribe.com/output/5270247
• Publisher URL: https://www.mdpi.com/1999-4915/13/2/234