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Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus.
Viruses. 2021 02 03; 13(2)V

Abstract

The long-term control strategy of SARS-CoV-2 and other major respiratory viruses needs to include 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 antivirals in use or development for any disease bears testament to the challenges of antiviral development. 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 infections as in co-infections. Post-infection oral gavage of acid-stable TG protected mice against a 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.

Authors+Show Affiliations

School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Nottingham LE12 5RD, UK.School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Nottingham LE12 5RD, UK.The Pirbright Institute, Ash Road, Pirbright, Woking GU24 0NF, UK.Animal and Plant Health Agency (APHA), Weybridge, Woodham Lane, Addlestone KT15 3NB, UK.Key Laboratory of Animal Epidemiology, Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, China.Animal and Plant Health Agency (APHA), Weybridge, Woodham Lane, Addlestone KT15 3NB, UK.Key Laboratory of Animal Epidemiology, Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, China.School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Nottingham LE12 5RD, UK.School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Nottingham LE12 5RD, UK.Animal and Plant Health Agency (APHA), Weybridge, Woodham Lane, Addlestone KT15 3NB, UK.School of Biosciences, University of Nottingham, Sutton Bonington, Nottingham LE12 5RD, UK.School of Pharmacy, University of Nottingham, University Park, Nottingham NG7 2RD, UK.School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK.School of Medicine, University of Nottingham, University Park, Nottingham NG7 2RD, UK.Animal and Plant Health Agency (APHA), Weybridge, Woodham Lane, Addlestone KT15 3NB, UK.Key Laboratory of Animal Epidemiology, Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, China.School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Nottingham LE12 5RD, UK.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33546185

Citation

Al-Beltagi, Sarah, et al. "Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza a Virus." Viruses, vol. 13, no. 2, 2021.
Al-Beltagi S, Preda CA, Goulding LV, et al. Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus. Viruses. 2021;13(2).
Al-Beltagi, S., Preda, C. A., Goulding, L. V., James, J., Pu, J., Skinner, P., Jiang, Z., 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). https://doi.org/10.3390/v13020234
Al-Beltagi S, et al. Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza a Virus. Viruses. 2021 02 3;13(2) PubMed PMID: 33546185.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus. AU - Al-Beltagi,Sarah, AU - Preda,Cristian Alexandru, AU - Goulding,Leah V, AU - James,Joe, AU - Pu,Juan, AU - Skinner,Paul, AU - Jiang,Zhimin, AU - Wang,Belinda Lei, AU - Yang,Jiayun, AU - Banyard,Ashley C, AU - Mellits,Kenneth H, AU - Gershkovich,Pavel, AU - Hayes,Christopher J, AU - Nguyen-Van-Tam,Jonathan, AU - Brown,Ian H, AU - Liu,Jinhua, AU - Chang,Kin-Chow, Y1 - 2021/02/03/ PY - 2021/01/14/received PY - 2021/01/23/revised PY - 2021/01/26/accepted PY - 2021/2/6/entrez PY - 2021/2/7/pubmed PY - 2021/2/18/medline KW - SARS-CoV-2 KW - antiviral KW - broad-spectrum KW - coronavirus OC43 KW - influenza virus KW - inhibitor KW - innate immunity KW - mouse KW - oseltamivir KW - remdesivir KW - respiratory syncytial virus KW - ribavirin KW - thapsigargin JF - Viruses JO - Viruses VL - 13 IS - 2 N2 - The long-term control strategy of SARS-CoV-2 and other major respiratory viruses needs to include 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 antivirals in use or development for any disease bears testament to the challenges of antiviral development. 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 infections as in co-infections. Post-infection oral gavage of acid-stable TG protected mice against a 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. SN - 1999-4915 UR - https://www.unboundmedicine.com/medline/citation/33546185/Thapsigargin_Is_a_Broad-Spectrum_Inhibitor_of_Major_Human_Respiratory_Viruses:_Coronavirus,_Respiratory_Syncytial_Virus_and_Influenza_A_Virus. L2 - https://www.mdpi.com/resolver?pii=v13020234 DB - PRIME DP - Unbound Medicine ER -