Thapsigargin repurposing for COVID-19

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. It was recently shown 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 [1] the authors from UK demonstrate 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, TG (or its derivatives) is a promising broad-spectrum inhibitor against SARS-CoV-2, OC43, RSV and influenza virus.

Thapsigargin, a sesquiterpene lactone, raises cytosolic (intracellular) calcium concentration by blocking the ability of the cell to pump calcium into the sarcoplasmic and endoplasmic reticula. Store-depletion can secondarily activate plasma membrane calcium channels, allowing an influx of calcium into the cytosol.

Thapsigargin/gamma-CD complex was used to extend the lifespan in C. elegans worms [2].

1. Al-Beltagi S, Preda CA, Goulding LV, James J, Pu J, Skinner P, Jiang Z, Wang BL, Yang J, Banyard AC, Mellits KH, Gershkovich P, Hayes CJ, Nguyen-Van-Tam J, Brown IH, Liu J, Chang K-C. Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus. Viruses. 2021; 13(2):234. https://doi.org/10.3390/v13020234
2. García-Casas P, Arias-del -Val J, Alvarez -Illera P, Fonteriz RI, Montero M and Alvarez J (2018) Inhibition of Sarco-Endoplasmic Reticulum Ca²⁺ ATPase Extends the Lifespan in C. elegans Worms. Front. Pharmacol. 9:669. https://doi.org/10.3389/fphar.2018.00669