An enzyme inhibitor is a medication or compound designed to block the activity of a specific enzyme in the body. Enzymes are proteins that accelerate chemical reactions, converting molecules into products. Inhibitors function by binding to these enzymes, preventing or reducing their efficiency. This targeted action allows enzyme inhibitors to regulate biological processes, making them valuable in treating various diseases.
Understanding Dipeptidyl Peptidase 1 (DPP1)
Dipeptidyl Peptidase 1 (DPP1), also known as Cathepsin C (CatC), is a lysosomal cysteine protease found throughout the body. High levels are present in the lungs, spleen, kidneys, liver, and various immune cells such as neutrophils, mast cells, and monocytes. Its primary natural role involves activating certain proteases, which are enzymes that break down proteins.
DPP1 specifically cleaves two amino acid residues from the N-terminus of inactive protease precursors, transforming them into their active forms. These activated proteases, including neutrophil elastase, proteinase 3, cathepsin G, mast cell chymase, tryptase, and granzymes A and B, are crucial for normal immune function. For instance, neutrophil serine proteases (NSPs) are stored in neutrophils and are released to fight infections and manage inflammation.
While these activated proteases are important for defense, their overactivity or dysregulation can lead to various health problems. Excessive release of NSPs, for example, can cause tissue damage and worsen inflammatory conditions. This imbalance between proteases and their natural inhibitors contributes to the progression of many inflammatory diseases, suggesting DPP1 inhibition as a therapeutic target.
How DPP1 Inhibitors Work
DPP1 inhibitors function by specifically targeting and binding to the DPP1 enzyme, thereby reducing or blocking its activity. DPP1 activates several proteases, such as neutrophil elastase, cathepsin G, and proteinase-3, by cleaving a dipeptide from their N-terminus during maturation in the bone marrow. By preventing this activation, DPP1 inhibitors ensure these proteases remain in their inactive, precursor forms.
This mechanism leads to a reduction in the overall levels of active proteases, particularly neutrophil serine proteases (NSPs), which are stored within neutrophil granules. When neutrophils migrate to sites of inflammation or infection, they release these proteases. If their activation is curbed by a DPP1 inhibitor, harmful inflammation and tissue damage can be significantly reduced. For example, a DPP1 inhibitor like brensocatib has been shown to reduce the activity of neutrophil elastase, proteinase 3, and cathepsin G in sputum, directly supporting its mechanism of action in reducing inflammation.
Medical Conditions Targeted by DPP1 Inhibitors
DPP1 inhibitors are being investigated as a therapeutic approach for several medical conditions where excessive protease activity contributes to disease pathology.
Netherton Syndrome
One such condition is Netherton syndrome, a rare genetic disorder caused by mutations in the SPINK5 gene, which leads to a deficiency of a protein called LEKTI. This deficiency results in uncontrolled activity of certain proteases in the skin, causing severe skin scaling, inflammation, and impaired skin barrier function.
Inflammatory Lung Diseases
DPP1 inhibitors are also a promising area for inflammatory lung diseases, where neutrophil serine proteases (NSPs) play a significant role in tissue damage.
##### Chronic Obstructive Pulmonary Disease (COPD)
In chronic obstructive pulmonary disease (COPD), elevated neutrophil counts and excessive NSP activity contribute to lung tissue destruction, mucus hypersecretion, and emphysema. By inhibiting DPP1, these medications aim to reduce the activation of NSPs like neutrophil elastase, thereby mitigating lung damage and inflammation. Studies have shown that DPP1 inhibition can lead to a reduction in neutrophil elastase activity in the blood, supporting its potential to modify disease progression.
##### Bronchiectasis
In bronchiectasis, a chronic lung disease characterized by airway destruction and persistent inflammation, increased DPP1 activity leads to an augmented production of active NSPs. Clinical trials, such as the WILLOW study, have shown that DPP1 inhibitors like brensocatib can significantly prolong the time to the first exacerbation and reduce the risk of exacerbations in patients with non-cystic fibrosis bronchiectasis, indicating a direct clinical benefit by reducing NSP activity in the airways.
##### Cystic Fibrosis (CF)
Cystic fibrosis (CF) is another chronic inflammatory lung disease where DPP1 inhibitors are relevant. In CF, thick mucus in the lungs leads to recurrent infections and inflammation, with NSPs contributing to mucus hyperconcentration and airway obstruction. By reducing the activity of these damaging proteases, DPP1 inhibitors may help alleviate lung damage and improve respiratory function.
Autoimmune Disorders
Beyond lung conditions, DPP1 inhibitors are also being explored for autoimmune disorders, such as rheumatoid arthritis and systemic lupus erythematosus, where overactive neutrophils and the release of harmful proteases contribute to inflammation and tissue destruction.