Lung Protection by Cathepsin C Inhibition: A New Hope for COVID-19 and ARDS?

Abstract

Cathepsin C (CatC) is a cysteine dipeptidyl aminopeptidase that activates most of tissue-degrading elastase-related serine proteases. Thus, CatC appears as a potential therapeutic target to impair protease-driven tissue degradation in chronic inflammatory and autoimmune diseases. A depletion of proinflammatory elastase-related proteases in neutrophils is observed in patients with CatC deficiency (Papillon–Lefèvre syndrome). To address and counterbalance unwanted effects of elastase-related proteases, chemical inhibitors of CatC are being evaluated in preclinical and clinical trials. Neutrophils may contribute to the diffuse alveolar inflammation seen in acute respiratory distress syndrome (ARDS) which is currently a growing challenge for intensive care units due to the outbreak of the COVID-19 pandemic. Elimination of elastase-related neutrophil proteases may reduce the progression of lung injury in these patients. Pharmacological CatC inhibition could be a potential therapeutic strategy to prevent the irreversible pulmonary failure threatening the life of COVID-19 patients.

Targeting Neutrophils to Treat Acute Respiratory Distress Syndrome in Coronavirus Disease

“…Brensocatib (also called INS1007 or AZD7986), a DPP1 inhibitor, was found to reduce NE activity in healthy humans ( Palmér et al, 2018 ) and is now in clinical trials for bronchiectasis (NCT03218917) and COVID-19 (EU clinical trial number EudraCT 2020-001643-13). The administration of DPP1 inhibitors may prevent ARDS progression caused by SARS-CoV-2 ( Korkmaz et al, 2020 ). Thus, DPP1 inhibitors are of interest in treating COVID-19 associated ARDS.…”

The race to treat COVID-19: Potential therapeutic agents for the prevention and treatment of SARS-CoV-2

“…In the last few months, the race to discover novel treatments for COVID -19 has immensely accelerated, and numerous peptides and small molecules have been recognized as encouraging therapeutic agents against SARS-CoV-2 [ [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] ]. Recently, the constrained peptides have received much attention in the area of drug development; however, a certain inherent admonition limits its use as a drug [ [46] , [47] , [48] ].…”

In Silico Screening of the DrugBank Database to Search for Possible Drugs against SARS-CoV-2

“…It was discovered in the 1960s and was thought to cause only a mild disease [ 5 ], but SARS-CoV-2 is the third emergence of a coronavirus in less than 20 years with important mortality rates. In this sense, SARS, MERS, and SARS-CoV-2 have death rates of 9.6%, 35.5% and 6.76%, respectively [ 8 , 9 ]. Early COVID-19 symptoms include fatigue, dry cough, muscle soreness, shortness of breath, and fever [ 10 ].…”

“…Early COVID-19 symptoms include fatigue, dry cough, muscle soreness, shortness of breath, and fever [ 10 ]. In severe cases of infections with SARS-CoV-2, patients require endotracheal intubation and mechanical ventilation, as they develop acute respiratory distress syndrome, pulmonary oedema, and severe pneumonia, causing death from sepsis shock, respiratory, or multiple organ failures [ 8 , 11 ].…”

“…Currently, there is no effective treatment available for CoV infections, including COVID-19 [ 14 ]. Therefore, efforts to create new therapies, such as antiviral medication or vaccines, are vital to reduce mortality, reactivate the economy, and return to a normal lifestyle [ 4 , 8 , 12 , 17 ].…”