Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus
Sarah Al-Beltagi,
Cristian Alexandru Preda,
Leah V. Goulding,
Joe James,
Juan Pu,
Paul Skinner,
Zhimin Jiang,
Belinda Lei Wang,
Jiayun Yang,
Ashley C. Banyard,
Kenneth H. Mellits,
Pavel Gershkovich,
Christopher J. Hayes,
Jonathan Nguyen-Van-Tam,
Ian H. Brown,
Jinhua Liu,
Kin-Chow Chang
Affiliations
Sarah Al-Beltagi
School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Nottingham LE12 5RD, UK
Cristian Alexandru Preda
School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Nottingham LE12 5RD, UK
Leah V. Goulding
The Pirbright Institute, Ash Road, Pirbright, Woking GU24 0NF, UK
Joe James
Animal and Plant Health Agency (APHA), Weybridge, Woodham Lane, Addlestone KT15 3NB, UK
Juan Pu
Key Laboratory of Animal Epidemiology, Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, China
Paul Skinner
Animal and Plant Health Agency (APHA), Weybridge, Woodham Lane, Addlestone KT15 3NB, UK
Zhimin Jiang
Key Laboratory of Animal Epidemiology, Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, China
Belinda Lei Wang
School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Nottingham LE12 5RD, UK
Jiayun Yang
School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Nottingham LE12 5RD, UK
Ashley C. Banyard
Animal and Plant Health Agency (APHA), Weybridge, Woodham Lane, Addlestone KT15 3NB, UK
Kenneth H. Mellits
School of Biosciences, University of Nottingham, Sutton Bonington, Nottingham LE12 5RD, UK
Pavel Gershkovich
School of Pharmacy, University of Nottingham, University Park, Nottingham NG7 2RD, UK
Christopher J. Hayes
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
Jonathan Nguyen-Van-Tam
School of Medicine, University of Nottingham, University Park, Nottingham NG7 2RD, UK
Ian H. Brown
Animal and Plant Health Agency (APHA), Weybridge, Woodham Lane, Addlestone KT15 3NB, UK
Jinhua Liu
Key Laboratory of Animal Epidemiology, Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, China
Kin-Chow Chang
School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Nottingham LE12 5RD, UK
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.
