Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus
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 o...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-02-01
|
| Series: | Viruses |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4915/13/2/234 |
| _version_ | 1797415981141721088 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Sarah Al-Beltagi |
| collection | DOAJ |
| description | 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) Ca<sup>2+</sup> 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. |
| first_indexed | 2024-03-09T05:57:18Z |
| format | Article |
| id | doaj.art-70cee23f37a34bc2a05f7b8bb21355cb |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-09T05:57:18Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-70cee23f37a34bc2a05f7b8bb21355cb2023-12-03T12:12:39ZengMDPI AGViruses1999-49152021-02-0113223410.3390/v13020234Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A VirusSarah Al-Beltagi0Cristian Alexandru Preda1Leah V. Goulding2Joe James3Juan Pu4Paul Skinner5Zhimin Jiang6Belinda Lei Wang7Jiayun Yang8Ashley C. Banyard9Kenneth H. Mellits10Pavel Gershkovich11Christopher J. Hayes12Jonathan Nguyen-Van-Tam13Ian H. Brown14Jinhua Liu15Kin-Chow Chang16School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Nottingham LE12 5RD, UKSchool of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Nottingham LE12 5RD, UKThe Pirbright Institute, Ash Road, Pirbright, Woking GU24 0NF, UKAnimal and Plant Health Agency (APHA), Weybridge, Woodham Lane, Addlestone KT15 3NB, UKKey Laboratory of Animal Epidemiology, Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, ChinaAnimal and Plant Health Agency (APHA), Weybridge, Woodham Lane, Addlestone KT15 3NB, UKKey Laboratory of Animal Epidemiology, Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, ChinaSchool of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Nottingham LE12 5RD, UKSchool of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Nottingham LE12 5RD, UKAnimal and Plant Health Agency (APHA), Weybridge, Woodham Lane, Addlestone KT15 3NB, UKSchool of Biosciences, University of Nottingham, Sutton Bonington, Nottingham LE12 5RD, UKSchool of Pharmacy, University of Nottingham, University Park, Nottingham NG7 2RD, UKSchool of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UKSchool of Medicine, University of Nottingham, University Park, Nottingham NG7 2RD, UKAnimal and Plant Health Agency (APHA), Weybridge, Woodham Lane, Addlestone KT15 3NB, UKKey Laboratory of Animal Epidemiology, Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, ChinaSchool of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Nottingham LE12 5RD, UKThe 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) Ca<sup>2+</sup> 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.https://www.mdpi.com/1999-4915/13/2/234thapsigargininhibitorantiviralSARS-CoV-2coronavirus OC43respiratory syncytial virus |
| spellingShingle | 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 Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus Viruses thapsigargin inhibitor antiviral SARS-CoV-2 coronavirus OC43 respiratory syncytial virus |
| title | Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus |
| title_full | Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus |
| title_fullStr | Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus |
| title_full_unstemmed | Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus |
| title_short | Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus |
| title_sort | thapsigargin is a broad spectrum inhibitor of major human respiratory viruses coronavirus respiratory syncytial virus and influenza a virus |
| topic | thapsigargin inhibitor antiviral SARS-CoV-2 coronavirus OC43 respiratory syncytial virus |
| url | https://www.mdpi.com/1999-4915/13/2/234 |
| work_keys_str_mv | AT sarahalbeltagi thapsigarginisabroadspectruminhibitorofmajorhumanrespiratoryvirusescoronavirusrespiratorysyncytialvirusandinfluenzaavirus AT cristianalexandrupreda thapsigarginisabroadspectruminhibitorofmajorhumanrespiratoryvirusescoronavirusrespiratorysyncytialvirusandinfluenzaavirus AT leahvgoulding thapsigarginisabroadspectruminhibitorofmajorhumanrespiratoryvirusescoronavirusrespiratorysyncytialvirusandinfluenzaavirus AT joejames thapsigarginisabroadspectruminhibitorofmajorhumanrespiratoryvirusescoronavirusrespiratorysyncytialvirusandinfluenzaavirus AT juanpu thapsigarginisabroadspectruminhibitorofmajorhumanrespiratoryvirusescoronavirusrespiratorysyncytialvirusandinfluenzaavirus AT paulskinner thapsigarginisabroadspectruminhibitorofmajorhumanrespiratoryvirusescoronavirusrespiratorysyncytialvirusandinfluenzaavirus AT zhiminjiang thapsigarginisabroadspectruminhibitorofmajorhumanrespiratoryvirusescoronavirusrespiratorysyncytialvirusandinfluenzaavirus AT belindaleiwang thapsigarginisabroadspectruminhibitorofmajorhumanrespiratoryvirusescoronavirusrespiratorysyncytialvirusandinfluenzaavirus AT jiayunyang thapsigarginisabroadspectruminhibitorofmajorhumanrespiratoryvirusescoronavirusrespiratorysyncytialvirusandinfluenzaavirus AT ashleycbanyard thapsigarginisabroadspectruminhibitorofmajorhumanrespiratoryvirusescoronavirusrespiratorysyncytialvirusandinfluenzaavirus AT kennethhmellits thapsigarginisabroadspectruminhibitorofmajorhumanrespiratoryvirusescoronavirusrespiratorysyncytialvirusandinfluenzaavirus AT pavelgershkovich thapsigarginisabroadspectruminhibitorofmajorhumanrespiratoryvirusescoronavirusrespiratorysyncytialvirusandinfluenzaavirus AT christopherjhayes thapsigarginisabroadspectruminhibitorofmajorhumanrespiratoryvirusescoronavirusrespiratorysyncytialvirusandinfluenzaavirus AT jonathannguyenvantam thapsigarginisabroadspectruminhibitorofmajorhumanrespiratoryvirusescoronavirusrespiratorysyncytialvirusandinfluenzaavirus AT ianhbrown thapsigarginisabroadspectruminhibitorofmajorhumanrespiratoryvirusescoronavirusrespiratorysyncytialvirusandinfluenzaavirus AT jinhualiu thapsigarginisabroadspectruminhibitorofmajorhumanrespiratoryvirusescoronavirusrespiratorysyncytialvirusandinfluenzaavirus AT kinchowchang thapsigarginisabroadspectruminhibitorofmajorhumanrespiratoryvirusescoronavirusrespiratorysyncytialvirusandinfluenzaavirus |