Camostat pancreatitis drug inhibits new SARS-CoV-2 inhibitors identified in the upper respiratory tract.
There are no available treatments developed for the treatment of COVID-19. Reproduction of a drug already available for COVID-19 treatment is an attractive option to shorten the road to treatment improvement.
The drug Camostat may be suitable. Camostat suppresses antiviral activity by inhibiting the protease TMPRSS2, which is used by SARS-CoV-2 for cell entry.
However, it was not previously known whether SARS-CoV-2 can use TMPRSS2-associated proteases for cell entry and whether these proteases can be inhibited by Camostat. Furthermore, it was unclear whether Camostat metabolization affects antiviral activity.
An international team of researchers surrounds Markus Hoffmann and Stefan Pöhlmann from the German Primate Center (DPZ) – The Leibniz Institute for Primary Research has now shown that SARS-CoV-2 can secrete several proteins related to TMPRSS2 used to activate it.
These proteases are secreted in the upper respiratory tract and are blocked by Camostat. In addition, the researchers found that Camostat and its major metabolite GBPA inhibit SARS-CoV-2 infection in primary human lung tissue.
These findings support the further development of Camostat and related fertilizers for the treatment of COVID-19 (EBioMedicine).
SARS-CoV-2 is responsible for activation by the cellular protease TMPRSS2 to capture lung cells. Researchers from the DPZ Disease Biology Unit previously recorded that the drugs camostat and nafamostat, which are used in Japan to treat inflammation in the pancreas, prevent SARS-CoV-2 infection by ‘blocking TMPRSS2.
However, it was not known whether Camostat metabolites also inhibit SARS-CoV-2 and whether the TMPRSS2-associated protease virus can be used for potentially malignant Camostat infection.
An international team of researchers around Markus Hoffmann and Stefan Pöhlmann from the DPZ’s Disease Biology Unit have now shown that SARS-CoV-2 can use several TMPRSS2-related proteins for disease, including TMPRSS11D and TMPRSS13.
These proteins may support viral transmission in the upper respiratory tract and Camostat is inhibited. This finding indicates that a switch to operators other than TMPRSS2 may not allow the virus to reproduce in the presence of Camostat.
The researchers could show that not only Camostat but also Camostat-metabolite inhibitor, GBPA, inhibits TMPRSS2 and SARS-CoV-2 infection.
“In the human body, Camostat is rapidly converted to GBPA. Therefore, it was crucial to show that it is not only Camostat but also GBPA that is performing anti-virus activity,” said Stefan Pöhlmann, head of Unit DPZ Disease Biology. Markus Hoffmann, the first author of the study, says: “Our results suggest that Camostat / GBPA may induce antiviral activity in patients. However, for effective treatment of COVID-19, it may be that a higher dose of Camostat is required compared to the treatment of pancreatitis. “
Inhibition of SARS-CoV-2 by Camostat was first demonstrated using the Calu-3 lung cell line. The participation of Armin Braun, Fraunhofer ITEM, Hannover, and Danny Jonigk, Institute of Pathology at MHH, allowed the consortium to analyze the antiviral activity of Camostat in ex vivo human lung tissue.
Camostat and GBPA inhibited SARS-CoV-2 infection in lung tissue and Nafamostat had increased antiviral activity.
Therefore, the team of the Disease Biology Unit and Armin Braun Laboratory are investigating how Nafamostat can be delivered directly into the human lung for increased antiviral activity. This project is financially supported by the Bundesministerium für Bildung und Forschung (BMBF) (RENACO project, Nafamostatmesylat Reproduction for the treatment of COVID-19).
Our results on Camostat and GBPA antiviral activity are relevant outside of COVID-19 treatment. TMPRSS2 plays an important role in other respiratory diseases. Therefore, Camostat could also be used successfully to treat the flu. “
Markus Hoffmann, First Author Study, German Prime Minister’s Center (DPZ) – Leibniz Institute
Source:
Deutsches Primatenzentrum (DPZ) / German Primate Center
Magazine Reference:
Hoffmann, M .., et al. (2021) Camostat mesylate inhibits SARS-CoV-2 activity by TMPRSS2-associated proteases and its metabolite GBPA exerts antiviral activity. EBioMedicine. doi.org/10.1016/j.ebiom.2021.103255.