Protease-Specific Biomarkers to Analyse Protease Inhibitors for Emphysema Associated with Alpha 1-Antitrypsin Deficiency. An Overview of Current Approaches

Viglio, Simona; Bak, Elisabeth G; Schouten, Iris G.M.; Iadarola, Paolo; Stolk, Jan

doi:10.3390/ijms22031065

Cited by 9 publications

(3 citation statements)

References 85 publications

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“…Measuring NE and PR3 activities as a treatment outcome is particularly important when investigating the treatment effects of chronic neutrophilic diseases, such as AATD, where these enzymes are considered primary drivers of the disease process. To date, assessing in vivo NE and PR3 activity has been made difficult by the broad range of shared substrates and the generation of non-specific cleavage products ( Viglio et al, 2021 ). We previously showed the specificity and reliability of the fibrinogenic peptides AαVal 360 and AαVal 541 as markers of NE and PR3, respectively ( Carter et al, 2011 ; Newby et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

A novel in vitro cell model of the proteinase/antiproteinase balance observed in alpha-1 antitrypsin deficiency

Chen,

Crisford,

Scott

et al. 2024

Front. Pharmacol.

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Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition resulting from mutations in the alpha-1 antitrypsin (AAT) protein, a major systemic antiproteinase, resulting in reduced/no release of AAT, disrupting the proteinase/antiproteinase balance. A sustained imbalance can cause structural changes to the lung parenchyma, leading to emphysema. Predicting and assessing human responses to potential therapeutic candidates from preclinical animal studies have been challenging. Our aims were to develop a more physiologically relevant in vitro model of the proteinase/antiproteinase balance and assess whether the data generated could better predict the efficacy of pharmacological candidates to inform decisions on clinical trials, together with expected biomarker responses.Methods: We developed an in vitro model assessing the proteinase/antiproteinase balance by the changes in the fibrinogen cleavage products of neutrophil elastase (NE) and proteinase 3 (PR3). This allowed the assessment of physiological and pharmaceutical neutrophil serine proteinase (NSP) inhibitors to determine the putative threshold at which the maximal effect is achieved.Results: AAT significantly reduced NE and PR3 activity footprints, with the maximal reduction achieved at concentrations above 10 μM. The inhibitor MPH966 alone also significantly reduced NE footprint generation in a concentration-dependent manner, leveling out above 100 nM but had no effect on the PR3 footprint. At levels of AAT consistent with AATD, MPH966 had an additive effect, reducing the NE activity footprint more than either inhibitor alone.Conclusion: Our results support an inhibitor threshold above which the activity footprint generation appears resistant to increasing dosage. Our model can support the testing of inhibitors, confirming activity biomarkers as indicators of likely pharmaceutical efficacy, the assessment of NSP activity in the pathophysiology of emphysema, and the likely function of biological or pharmacological inhibitors in disease management.

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Section: Discussionmentioning

confidence: 99%

A novel in vitro cell model of the proteinase/antiproteinase balance observed in alpha-1 antitrypsin deficiency

Chen,

Crisford,

Scott

et al. 2024

Front. Pharmacol.

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“…This observation underscores the neutrophil-specific anti-inflammatory potential of NSP inhibitors. Moreover, lack of alpha-1-antitrypsin, an endogenous NSP inhibitor, in patients with AATD (dysfunctional SERPINA1 gene, primarily found in the respiratory system) is characterized by severe respiratory problems caused by excessive degradation of lung parenchyma, increased inflammation and increased susceptibility to infections ( 44 ). On the one hand, the release of NSP inhibitors by S. aureus prevents degradation of PSMs and other virulence factors, which could exacerbate inflammation.…”

Section: Discussionmentioning

confidence: 99%

Staphylococcus aureus Depends on Eap Proteins for Preventing Degradation of Its Phenol-Soluble Modulin Toxins by Neutrophil Serine Proteases

et al. 2021

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Neutrophil granulocytes act as a first line of defense against pathogenic staphylococci. However, Staphylococcus aureus has a remarkable capacity to survive neutrophil killing, which distinguishes it from the less-pathogenic Staphylococcus epidermidis. Both species release phenol-soluble modulin (PSM) toxins, which activate the neutrophil formyl-peptide receptor 2 (FPR2) to promote neutrophil influx and phagocytosis, and which disrupt neutrophils or their phagosomal membranes at high concentrations. We show here that the neutrophil serine proteases (NSPs) neutrophil elastase, cathepsin G and proteinase 3, which are released into the extracellular space or the phagosome upon neutrophil FPR2 stimulation, effectively degrade PSMs thereby preventing their capacity to activate and destroy neutrophils. Notably, S. aureus, but not S. epidermidis, secretes potent NSP-inhibitory proteins, Eap, EapH1, EapH2, which prevented the degradation of PSMs by NSPs. Accordingly, a S. aureus mutant lacking all three NSP inhibitory proteins was less effective in activating and destroying neutrophils and it survived less well in the presence of neutrophils than the parental strain. We show that Eap proteins promote pathology via PSM-mediated FPR2 activation since murine intraperitoneal infection with the S. aureus parental but not with the NSP inhibitors mutant strain, led to a significantly higher bacterial load in the peritoneum and kidneys of mFpr2-/- compared to wild-type mice. These data demonstrate that NSPs can very effectively detoxify some of the most potent staphylococcal toxins and that the prominent human pathogen S. aureus has developed efficient inhibitors to preserve PSM functions. Preventing PSM degradation during infection represents an important survival strategy to ensure FPR2 activation.

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“…As a result, a transition state analogue is formed. The inhibitory effect of ONO-6818 is specific and reversible 57 .…”

Section: Hne Inhibitormentioning

confidence: 96%

Review of Serine Protease Inhibitors: Development and Applications

Ramadan

2023

Bulletin of Pharmaceutical Sciences Assiut University

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A class of enzymes known as proteases is responsible for catalyzing the breakdown of covalent peptide bonds. Proteases account for almost 2% of the genes in humans, infectious organisms, and other forms of life. Serine proteases, so named because they have a nucleophilic serine residue at the active site, make for nearly one-third of all proteases. Although digesting is their primary role in humans, they also play roles in immunological response, apoptosis, inflammation, blood coagulation, and signal transduction. They are therefore very attractive biological targets for the design of pharmacological molecules that can modulate their activity.This review presents a description of the catalytic activity and structure of serine proteases, and the different strategies to develop inhibitors. Serine protease inhibitors targeting thrombin, FXa, and human neutrophil elastase (HNE), and dipeptidylprotease-4 (DPP4) will be described. It includes therapeutically applied, and those drugs which are still under investigation in clinical trials in the last two decades.

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Protease-Specific Biomarkers to Analyse Protease Inhibitors for Emphysema Associated with Alpha 1-Antitrypsin Deficiency. An Overview of Current Approaches

Cited by 9 publications

References 85 publications

A novel in vitro cell model of the proteinase/antiproteinase balance observed in alpha-1 antitrypsin deficiency

A novel in vitro cell model of the proteinase/antiproteinase balance observed in alpha-1 antitrypsin deficiency

Staphylococcus aureus Depends on Eap Proteins for Preventing Degradation of Its Phenol-Soluble Modulin Toxins by Neutrophil Serine Proteases

Review of Serine Protease Inhibitors: Development and Applications

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