A Dipeptidyl Peptidase 1 (DPP1) inhibitor is a type of medication that targets an enzyme deeply involved in the body’s inflammatory response. This drug class is designed to modulate a specific part of the immune system responsible for generating powerful destructive molecules. The overall goal of using these inhibitors is to reduce the chronic and often severe damage caused by excessive or misdirected inflammation in various diseases. By intervening at an early stage of the inflammatory cascade, these drugs offer a new approach to protecting tissues, particularly in the lungs, from progressive deterioration.
The Biological Role of DPP1
The enzyme Dipeptidyl Peptidase 1 (DPP1), also known as Cathepsin C (CatC), plays a key function within the body’s primary defense cells, the neutrophils. DPP1 resides within the cell’s internal compartments. Its physiological role is to act as a molecular activating “scissors” for a specific group of immune proteins called neutrophil serine proteases (NSPs).
This activation occurs when the neutrophil is still maturing inside the bone marrow. DPP1 precisely cleaves small segments from the inactive precursor forms of the NSPs, transforming them into their fully active, destructive state. The three most potent members of this activated group are Neutrophil Elastase (NE), Cathepsin G (CatG), and Proteinase 3 (PR3). These mature proteases are then packaged into granules, ready for the neutrophil to release upon encountering an invading pathogen, such as bacteria.
However, when neutrophils are recruited to areas of chronic inflammation, they can release these powerful enzymes into healthy tissues. This uncontrolled release of NE, CatG, and PR3 leads to a destructive cycle, causing structural damage to the lung tissue and perpetuating the inflammatory state. This uncontrolled proteolytic activity is a major factor in the progression of several chronic inflammatory diseases.
How Inhibitors Block Inflammatory Damage
DPP1 inhibitors function by selectively binding to and blocking the active site of the DPP1 enzyme. This pharmacological intervention is considered an “upstream” approach because it acts at the source of the destructive capacity, rather than trying to neutralize the proteases after they have been released. Neutrophils continue to be produced and function normally, but they leave the bone marrow with inactive forms of the serine proteases stored in their granules.
By preventing the activation of NE, CatG, and PR3, the inhibitors significantly lower the concentration of active proteases released into the tissues. This reduction in proteolytic activity breaks the self-perpetuating cycle of inflammation and tissue destruction. The cascade is interrupted: DPP1 is blocked, NSPs remain inactive, and chronic tissue damage is mitigated.
Blocking DPP1 also has broader anti-inflammatory effects beyond reducing protease release. Studies suggest that DPP1 inhibition can reduce the formation of Neutrophil Extracellular Traps (NETs), a web-like structure of DNA and proteins that can contribute to tissue damage. Furthermore, the reduction in active proteases can diminish the degradation of the extracellular matrix, the structural scaffolding of the lungs.
Treating Diseases Driven by Neutrophil Activity
DPP1 inhibitors are highly relevant for diseases characterized by excessive neutrophil activity. Non-Cystic Fibrosis Bronchiectasis (NCFBE) is a primary target. Chronic bacterial infection in NCFBE leads to a continuous recruitment of neutrophils to the airways, which repeatedly release activated proteases. This causes permanent widening and damage to the airways, which exacerbates the cycle of infection and inflammation.
In NCFBE, DPP1 inhibition aims to reduce the frequency of pulmonary exacerbations, which require antibiotic treatment and lead to lung function decline. Cystic Fibrosis (CF) patients also experience severe, chronic airway inflammation driven by high levels of active NSPs. The presence of active NE, CatG, and PR3 in CF airways is strongly associated with disease progression and rapid loss of lung function.
Severe inflammatory lung diseases, such as emphysema related to Alpha-1 Antitrypsin Deficiency (AATD), are rooted in an imbalance between destructive proteases and the body’s natural inhibitors. In AATD, a genetic lack of the antiprotease allows active NSPs to overwhelm the lungs and cause tissue destruction. By reducing the total amount of active NSPs through DPP1 inhibition, this therapeutic strategy directly addresses the protease side of the imbalance. This approach represents a shift from managing symptoms to modifying the core underlying disease process.
Specific Drugs in Development
The most advanced DPP1 inhibitor molecule is Brensocatib. Brensocatib is an oral, reversible inhibitor that has demonstrated efficacy in large-scale clinical trials. It has been evaluated in adults with NCFBE, a condition with no previously approved targeted treatment.
The Phase 3 ASPEN study, involving over 1,700 patients, confirmed the drug’s benefit in NCFBE. This trial showed that patients receiving Brensocatib experienced a significant reduction in the rate of pulmonary exacerbations annually, with reductions of approximately 20% compared to placebo. The drug also successfully prolonged the time until a patient experienced their first exacerbation.
Following these positive results, Brensocatib has received regulatory designations to expedite its review and has been submitted for approval for NCFBE treatment. If approved, it would be the first medication specifically targeting the underlying neutrophil-driven inflammation in this disease. Other DPP1 inhibitors, such as BI 1291583 and HSK31858, are also progressing through clinical development, suggesting a growing class of therapies focused on this novel mechanism.