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Neutrophils have a critical role in the innate immune response to infection and the control of inflammation. A key component of this process is the release of neutrophil serine proteases (NSPs), primarily neutrophil elastase, proteinase 3, cathepsin G, and NSP4, which have essential functions in immune modulation and tissue repair following injury. Normally, NSP activity is controlled and modulated by endogenous antiproteases. However, disruption of this homeostatic relationship can cause diseases in which neutrophilic inflammation is central to the pathology, such as chronic obstructive pulmonary disease (COPD), alpha-1 antitrypsin deficiency, bronchiectasis, and cystic fibrosis, as well as many non-pulmonary pathologies. Although the pathobiology of these diseases varies, evidence indicates that excessive NSP activity is common and a principal mediator of tissue damage and clinical decline. NSPs are synthesized as inactive zymogens and activated primarily by the ubiquitous enzyme dipeptidyl peptidase 1, also known as cathepsin C. Preclinical data confirm that inactivation of this protease reduces activation of NSPs. Thus, pharmacological inhibition of dipeptidyl peptidase 1 potentially reduces the contribution of aberrant NSP activity to the severity and/or progression of multiple inflammatory diseases. Initial clinical data support this view. Ongoing research continues to explore the role of NSP activation by dipeptidyl peptidase 1 in different disease states and the potential clinical benefits of dipeptidyl peptidase 1 inhibition.

Trichinella spiralis dipeptidyl peptidase 1 (TsDPP1), or cysteine cathepsin C, is a secretory protein that is highly expressed during the infective larvae and adult worm stages in the intestines. The aim of this study was to investigate the mechanism by which recombinant TsDPP1 (rTsDPP1) activates macrophages M2 polarization and decreases macrophage cytotoxicity to kill newborn larvae via ADCC. RAW264.7 macrophages and murine peritoneal macrophages were used in this study. The results of the immunofluorescence test (IFT) and confocal microscopy showed that rTsDPP1 specifically bound to macrophages, and the binding site was localized on the cell membrane. rTsDPP1 activated macrophage M2 polarization, as demonstrated by high expression levels of Arg1 (M2 marker) and M2-related genes (IL-10, TGF-β, CD206 and Arg1) and high numbers of CD206 + macrophages. Furthermore, the expression levels of p-STAT6, STAT6 and PPARγ were obviously increased in rTsDPP1-treated macrophages, which were evidently abrogated by using a STAT6 inhibitor (AS1517499) and PPARγ antagonist (GW9662). The results indicated that rTsDPP1 promoted macrophage M2 polarization through the STAT6/PPARγ pathway. Griess reaction results revealed that rTsDPP1 suppressed LPS-induced NO production in macrophages. qPCR and flow cytometry results showed that rTsDPP1 downregulated the expression of FcγR I (CD64) in macrophages. The ability of ADCC to kill newborn larvae was significantly decreased in rTsDPP1-treated macrophages, but AS1517499 and GW9662 restored its killing capacity. Our results demonstrated that rTsDPP1 induced macrophage M2 polarization, upregulated the expression of anti-inflammatory cytokines, and inhibited macrophage-mediated ADCC via activation of the STAT6/PPARγ pathway, which is beneficial to the parasitism and immune evasion of this nematode.

Neutrophils have been implicated in initiating and perpetuating systemic lupus erythematosus and the resultant kidney damage in lupus nephritis (LN) patients, in part through an excessive release of neutrophil serine proteases (NSPs). NSP zymogens are activated by dipeptidyl peptidase 1 (DPP1) during neutrophil maturation and released by mature neutrophils in response to inflammatory stimuli. Thus, a potential strategy to attenuate disease progression in LN would be to inhibit DPP1. We tested whether brensocatib, a highly selective and reversible DPP1 inhibitor, could mitigate LN progression in an interferon-alpha (IFNα)-accelerated NZB/W F1 mouse model. To confirm brensocatib’s pharmacodynamic effect on NSPs in this mouse strain, repeated dose studies were conducted for 7 and 14 days in naïve NZB/W F1 mice via oral gavage twice a day. Brensocatib at 2 and 20 mg/kg/day achieved a significant reduction in bone marrow NSP activities after 7 days of daily administration. To initiate LN disease progression, the mice were injected with an IFNα-expressing adenovirus. After 2 weeks, three brensocatib doses (or vehicle) were administered for 6 more weeks. Throughout the 8-week study, brensocatib treatment (20 mg/kg/day) significantly reduced the occurrence of severe proteinuria compared to the vehicle control. Brensocatib treatment also entailed a significant reduction in the urine albumin-to-creatinine ratio, indicating decreased kidney damage, as well as a significant reduction in blood urea nitrogen level, suggesting improved renal function. Based on kidney histopathology analysis, brensocatib treatment significantly lowered both the renal tubular protein score and the nephropathy score compared to the vehicle group. A trend towards reduced glomerulonephritis score with brensocatib treatment was also observed. Lastly, brensocatib significantly reduced LN mouse kidney infiltration by various inflammatory cells. In conclusion, these results suggest that brensocatib alters disease progression in LN mice and warrant further evaluation of DPP1 inhibition in LN.

Dipeptidyl peptidase 1 (DPP1) inhibitors constitute a major advance in respiratory disease therapeutics. Through selective blockade of neutrophil serine protease (NSP) activation, these agents establish novel treatment paradigms for inflammatory respiratory conditions characterized by neutrophil-driven pathology. This comprehensive review examines the development status, clinical efficacy, and safety profile of DPP1 inhibitors in neutrophil-driven diseases, particularly non-cystic fibrosis bronchiectasis (NCFBE) and chronic obstructive pulmonary disease (COPD). Leading compounds including brensocatib, BI 1291583, and HSK31858 have demonstrated substantial clinical efficacy. In the pivotal WILLOW Phase II trial, brensocatib significantly extended time to first exacerbation (hazard ratio 0.58–0.62, p < 0.05) in bronchiectasis patients. The subsequent ASPEN Phase III trial confirmed these findings, with brensocatib reducing annualized exacerbation rates by 21% (10 mg) and 19% (25 mg) compared to placebo (adjusted p = 0.004 and p = 0.005, respectively). Similarly, HSK31858 demonstrated comparable efficacy in Chinese patients, reducing exacerbation risk by 48%–59% in the SAVE-BE trial. While the clinical phenotype observed in Papillon-Lefèvre syndrome (PLS) necessitates careful monitoring of skin and periodontal health during DPP1 inhibition therapy, clinical trials have shown these adverse events occur at low frequencies (1%–4%) and are predominantly mild to moderate in severity. Future research priorities include establishing standardized monitoring protocols for dermatological and periodontal health, developing biomarkers for patient stratification, validating long-term safety profiles, and optimizing combination treatment strategies. With brensocatib potentially becoming the first approved mechanism-specific therapy for bronchiectasis by mid-2025, DPP1 inhibitors represent a paradigm shift in managing neutrophil-mediated respiratory diseases.

Hidradenitis suppurativa (HS) is a chronic, recurrent inflammatory skin disease characterized by painful nodules, abscesses, and epithelialized tunnels, predominantly affecting flexural regions. With a global prevalence of approximately 1%, HS has a significant negative impact on quality of life. Multi-omics and histopathology studies have revealed a complex interplay between innate and adaptive immunity in HS, with neutrophils emerging as important drivers of inflammation. While therapies targeting TNF-α and IL-17 isoforms offer a degree of benefit, significant unmet need remains. Neutrophil signatures in HS lesions and the circulation underscore the rationale for selective modulation of neutrophil function. Strategies advancing through clinical trials include inhibition of chemokine-mediated trafficking, neutrophil serine protease inactivation and suppression of neutrophil extracellular traps (NETs), which amplify inflammatory and autoimmune responses. These emerging therapies mark a significant shift toward targeted neutrophil modulation, offering new opportunities to improve outcomes for patients with HS.

Brensocatib is a novel, oral, selective, reversible inhibitor of dipeptidyl peptidase 1 (DPP1), which activates several neutrophil serine proteases (NSPs), including neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (CatG) in the bone marrow during the early stage of neutrophil maturation. These NSPs are associated with pathogen destruction and inflammatory mediation; their dysregulated activation can result in excess secretion of active NSPs causing damaging inflammation and contributing to neutrophil-mediated inflammatory and autoimmune diseases. Pharmacological inhibition of DPP1 in the bone marrow could therefore represent an attractive strategy for these neutrophil-driven diseases. A completed Phase 2 trial in non-cystic fibrosis bronchiectasis patients (ClinicalTrials.gov number NCT03218917; EudraCT number: 2017-002533-32) indeed demonstrated that administration of brensocatib attenuated the damaging effects of chronic inflammation by inhibiting the downstream activation of NSPs. To support a range of preclinical programs and further understand how rodent species and strains may affect brensocatib’s pharmacokinetic (PK) profile and its pharmacodynamic (PD) effects on NE, PR3, and CatG, an extensive naïve dosing study with brensocatib at different dosing levels, frequencies, and durations was undertaken. Dose-dependent PK exposure responses (AUC and Cmax) were observed regardless of the rodent species and strain. Overall, mice showed greater reduction in NSP activities compared to rats. Both mice and rats dosed once daily (QD) had equivalent NSP activity reduction compared to BID (twice a day) dosing when the QD dose was 1.5-times the BID daily dose. For both mouse strains, CatG activity was reduced the most, followed by NE, then PR3; whereas, for both rat strains, PR3 activity was reduced the most, followed by CatG, and then NE. Maximum reduction in NSP activities was observed after ∼7 days and recoveries were nearly symmetrical. These results may facilitate future in vivo brensocatib study dosing considerations, such as the timing of prophylactic or therapeutic administration, choice of species, dosage and dosing frequency.

To ensure successful feeding tick saliva contains a number of inhibitory proteins that interfere with the host immune response and help to create a permissive environment for pathogen transmission. Among the potential targets of the salivary cystatins are two host cysteine proteases, cathepsin S, which is essential for antigen- and invariant chain-processing, and cathepsin C (dipeptidyl peptidase 1, DPP1), which plays a critical role in processing and activation of the granule serine proteases. Here, the effect of salivary cystatin OmC2 from was studied using differentiated MUTZ-3 cells as a model of immature dendritic cells of the host skin. Following internalization, cystatin OmC2 was initially found to inhibit the activity of several cysteine cathepsins, as indicated by the decreased rates of degradation of fluorogenic peptide substrates. To identify targets, affinity chromatography was used to isolate His-tagged cystatin OmC2 together with the bound proteins from MUTZ-3 cells. Cathepsins S and C were identified in these complexes by mass spectrometry and confirmed by immunoblotting. Furthermore, reduced increase in the surface expression of MHC II and CD86, which are associated with the maturation of dendritic cells, was observed. In contrast, human inhibitor cystatin C, which is normally expressed and secreted by dendritic cells, did not affect the expression of CD86. It is proposed that internalization of salivary cystatin OmC2 by the host dendritic cells targets cathepsins S and C, thereby affecting their maturation.

Background We aim to investigate comparative dementia risk associated with glucagon-like peptide-1 receptor agonists (GLP1-RAs), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and dipeptidyl peptidase-4 inhibitors (DPP4i) in adults aged ≥ 60 years with type 2 diabetes. Methods This target trial emulation cohort study used primary care electronic health records from the UK Clinical Practice Research Datalink. Initiators of GLP1-RAs, SGLT2i, or DPP4i aged ≥ 60 years with type 2 diabetes and without cognitive impairment were compared pairwise in three separate analyses. After propensity scores overlap weighting, 13,965 pairs of GLP1-RA versus DPP4i initiators (cohort entry: 2006–2022; mean age: 66.9 years), 25,533 pairs of SGLT2i versus DPP4i initiators (cohort entry: 2013–2022; mean age: 69.0 years), and 14,214 pairs of GLP1-RA versus SGLT2i initiators (cohort entry: 2013–2022; mean age: 67.9 years) were analyzed. The primary outcome was incident all-cause dementia. The primary analysis was an intention-to-treat analysis. A secondary as-treated analysis for continuous use was performed. Results In the intention-to-treat analysis, dementia risk was not different between GLP1-RA and DPP4i initiators (hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.87–1.04; rates: 6.29 versus 6.64 per 1000 person-years; mean follow-up: 6.54 years); however, continuous GLP1-RA versus DPP4i use was associated with a 21% lower risk (HR 0.79, 95% CI 0.64–0.97; rates: 3.64 versus 4.82; mean follow-up: 2.71 years). SGLT2i versus DPP4i initiation was associated with a 14% lower dementia risk in the intention-to-treat analysis (HR 0.86, 95% CI 0.79–0.94; rates: 4.83 versus 5.60; mean follow-up: 4.91 years), and the as-treated analysis showed greater risk reduction (HR 0.70, 95% CI 0.60–0.82; rates: 3.82 versus 5.46; mean follow-up: 2.43 years). Dementia risk was comparable between GLP1-RA versus SGLT2i in both intention-to-treat (HR 0.98, 95% CI 0.87–1.11; rates: 4.85 versus 4.95; mean follow-up: 5.09 years) and as-treated (HR 1.07, 95% CI 0.85–1.36; rates: 3.71 versus 3.56; mean follow-up: 2.40 years) analyses. Conclusions In people with type 2 diabetes aged ≥ 60 years, SGLT2i are associated with reduced dementia risk, but dementia risk reduction associated with the GLP1-RAs studied is less certain.

DBPR108 (prusogliptin) is a novel, orally bioavailable dipeptidyl peptidase-4 (DPP-4) inhibitor. This study investigated the pharmacokinetics and pharmacodynamic characteristics of DBPR108 tablets in patients with type 2 diabetes. In this randomized, parallel-group, open-label, phase I study, Chinese adults with type 2 diabetes, glycated hemoglobin of 7.0-9.5%, and body mass index of 19-35 kg/m were randomized 1:1:1 to once-daily DBPR108 50-, 100-, or 200-mg tablet groups. The primary endpoints included pharmacokinetic and pharmacodynamic characteristics after a single dose and multiple doses of DBPR108. In total, 30 patients were randomized with 10 patients in each group. DBPR108 was quickly absorbed with median time to reach the maximum plasma concentration of 1.5-4 h at steady state. Exposure to DBPR108 at steady-state increased dose proportionally with mean maximum steady-state plasma DBPR108 concentration during dosage intervals of 119, 256, and 567 ng/mL in the 50-, 100-, and 200-mg groups, respectively. Accumulation ratio of DBPR108 ranged from 0.85 to 1.3, and steady state was reached after four continuous daily doses. After multiple doses of DBPR108, maximum inhibitory efficacy of DPP-4 increased with higher dose levels ranging from 62.1 to 89.4%. Active glucagon-like peptide-1 levels increased after DBPR108 administration. In addition, six patients experienced treatment-emergent adverse events without leading to treatment interruption or discontinuation. DBPR108 was well tolerated in Chinese patients with type 2 diabetes, and both the pharmacokinetic and pharmacodynamic profiles support once-daily dosage regimens of DBPR108 in future studies. ClinicalTrials.gov (NCT05146869); registered 23 November 2021.

Abstract Abstract Individuals with diabetes are at increased risk for bacterial, mycotic, parasitic, and viral infections. The severe acute respiratory syndrome (SARS)-CoV-2 (also referred to as COVID-19) coronavirus pandemic highlights the importance of understanding shared disease pathophysiology potentially informing therapeutic choices in individuals with type 2 diabetes (T2D). Two coronavirus receptor proteins, angiotensin-converting enzyme 2 (ACE2) and dipeptidyl peptidase-4 (DPP4) are also established transducers of metabolic signals and pathways regulating inflammation, renal and cardiovascular physiology, and glucose homeostasis. Moreover, glucose-lowering agents such as the DPP4 inhibitors, widely used in subjects with T2D, are known to modify the biological activities of multiple immunomodulatory substrates. Here, we review the basic and clinical science spanning the intersections of diabetes, coronavirus infections, ACE2, and DPP4 biology, highlighting clinical relevance and evolving areas of uncertainty underlying the pathophysiology and treatment of T2D in the context of coronavirus infection. Graphical Abstract Graphical Abstract