Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial

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

“…In a large study of AATD patients, poor outcome of COVID-19 was more associated with nonrespiratory comorbidities than with genotype or respiratory function tests ( 55 ). Moreover, published clinical trials showed that intravenous α1AT or inhibition of cathepsin C, a dipeptidyl peptidase required for the maturation of NSPs into active enzymes, did not improve the clinical course of hospitalized COVID-19 patients ( 56 , 57 ). In conclusion, the use of NSP inhibitors in COVID-19 patients and interpretation of clinical trial data should be weighed and interpreted in the light of the antiviral and antiinflammatory effects of NSPs in SARS-CoV-2 infection shown here.…”

Neutrophil Extracellular Traps in Cardiovascular and Aortic Disease: A Narrative Review on Molecular Mechanisms and Therapeutic Targeting

“…Yet, the SARS-CoV-2 pandemic expedited a number of trials with compounds suited for directly or indirectly reducing NET burden in COVID-19 patients. While no statistical results were reported for the application of the NE inhibitor Alvelestat (ClinicalTrials.gov ID: NCT04539795), blockade of the NE activator dipeptidyl peptidase 1 by Brensocatib did not improve disease status of hospitalized COVID-19 patients [109]. Among established CVD treatments, the beta blocker metoprolol was shown to reduce NET release and ARDS-associated inflammation in critically ill COVID-19 patients [110].…”

“…Moreover, most of the therapeutic strategies targeting NETs in CVD have been tested in rodent models with regard to disease development, thus raising concerns about the translational applicability of the findings. While clinical trials with recombinant DNase gave promising results in the context of COVID-19 [79,120,121], the majority of NETtargeting clinical studies to date are based on drugs that act pleiotropically and they differ in their outcomes [109]. In a terminated clinical trial (NCT03250689) on chronic obstructive pulmonary disease, the CXCR2 antagonist danirixin was used to inhibit NET release as previously tested through in vitro and in vivo animal experiments [129].…”

Is neutrophilic inflammation treatable in COVID-19?

“…Measuring the activities of disease-associated immune modulators, such as proteases, might be a step towards personalised and timely therapeutic approaches for COVID-19. Although Keir and colleagues 5 have provided evidence in this trial that broad-spectrum targeting of neutrophil serine proteases is not beneficial for patients with COVID-19, we should remain open-minded that different approaches to precision-target neutrophils might enable improvement of clinical outcomes.…”

“…In The Lancet Respiratory Medicine, Holly R Keir and colleagues 5 test the hypothesis that blocking activation of multiple neutrophil serine proteases could improve outcomes in patients hospitalised with COVID-19 by limiting the injurious effects of neutrophilic inflammation. In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial involving 406 patients hospitalised with COVID-19, 192 participants in the intervention group were given brensocatib, an oral inhibitor of dipeptidyl peptidase-1 (DPP-1), which is an enzyme that activates neutrophil serine proteases.…”