Camostat Does Not Inhibit the Proteolytic Activity of Neutrophil Serine Proteases

Area of Science:

• Virology
• Immunology
• Biochemistry

Background:

• Coronavirus disease 2019 (COVID-19) can cause multi-organ failure, exacerbated by comorbidities and age.
• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into host cells involves spike protein binding to ACE2 and cleavage by TMPRSS2.
• Neutrophil serine proteases (NSPs) like CatG, NE, and PR3 are released during infection and contribute to immune responses but may also drive severe COVID-19 complications.

Purpose of the Study:

• To investigate the effect of camostat, a TMPRSS2 inhibitor, on NSPs.
• To determine if camostat can inhibit the activity of CatG, NE, and PR3.
• To identify the need for alternative serine protease inhibitors for managing severe COVID-19.

Main Methods:

• Assessing the catalytic activity of neutrophil serine proteases (CatG, NE, PR3).
• Testing the inhibitory effect of camostat on these NSPs in vitro.
• Comparing camostat's inhibition profile with its known activity against TMPRSS2.

Main Results:

• Camostat effectively inhibits SARS-CoV-2 entry by blocking TMPRSS2.
• Camostat demonstrated no inhibitory effect on the catalytic activity of CatG, NE, and PR3.
• This indicates that camostat does not target the NSPs implicated in COVID-19 pathogenesis.

Conclusions:

• The findings highlight that camostat is ineffective against NSPs.
• Additional selective serine protease inhibitors are required to target NSPs.
• Developing new inhibitors could mitigate severe COVID-19 outcomes, including thrombosis and autoimmunity.