Camostat Does Not Inhibit the Proteolytic Activity of Neutrophil Serine Proteases

Abstract

Coronavirus disease 2019 (COVID-19) can lead to multi-organ failure influenced by comorbidities and age. Binding of the severe acute respiratory syndrome coronavirus 2 spike protein (SARS-CoV-2 S protein) to angiotensin-converting enzyme 2 (ACE2), along with proteolytic digestion of the S protein by furin and transmembrane protease serine subtype 2 (TMPRSS2), provokes internalization of SARS-CoV-2 into the host cell. Productive infection occurs through viral replication in the cytosol and cell-to-cell transmission. The catalytic activity of TMPRSS2 can be blocked by the trypsin-like serine protease inhibitor camostat, which impairs infection by SARS-CoV-2. At the site of infection, immune cells, such as neutrophils, infiltrate and become activated, releasing neutrophil serine proteases (NSPs), including cathepsin G (CatG), neutrophil elastase (NE), and proteinase 3 (PR3), which promote the mounting of a robust immune response. However, NSPs might be involved in infection and the severe outcome of COVID-19 since the uncontrolled proteolytic activity is responsible for many complications, including autoimmunity, chronic inflammatory disorders, cardiovascular diseases, and thrombosis. Here, we demonstrate that camostat does not inhibit the catalytic activity of CatG, NE, and PR3, indicating the need for additional selective serine protease inhibitors to reduce the risk of developing severe COVID-19.

Neutrophil proteases are protective against SARS-CoV-2 by degrading the spike protein and dampening virus-mediated inflammation

“…In silico studies and experimental data based on small peptide cleavage suggest that NSPs can process SARS-CoV-2 S protein at the S1/S2 boundary; however, these studies did not investigate cleavage of full-length S protein and the resulting effect on viral entry is unknown (29)(30)(31)(32). Moreover, as active NSPs have been found in the lung of COVID-19 patients with ARDS, the use of NSP inhibitors, such as α1-antitrypsin (α1AT), has been proposed in COVID-19 patients and particularly in patients with cystic fibrosis or α1AT deficiency (33)(34)(35)(36). Here, we examined the proteolysis of SARS-CoV-2 S protein by CatG, NE, and PR3, and viral entry in vitro.…”

Special Issue “Drug Candidates for the Treatment of Infectious Diseases”

“…In the realm of viral infections, Assylbekova and colleagues were pioneers in reporting that camostat does not impede the proteolytic activity of neutrophil serine protease during SARS-CoV-2 infection [ 29 ]. Singh and Arkin detailed the impact of arapladib and flumatinib in obstructing the 3a ion channel linked to SARS-CoV-2 [ 30 ].…”