A patenting perspective on human neutrophil elastase (HNE) inhibitors (2014-2018) and their therapeutic applications

Crocetti, Letizia; Quinn, Mark T.; Schepetkin, Igor A.; Giovannoni, Maria Paola

doi:10.1080/13543776.2019.1630379

Cited by 55 publications

(46 citation statements)

References 133 publications

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“…HNE also conducts proteolysis and plays a significant role in several biological processes. Despite the positive attributes, overproduction and uncontrolled functioning of elastase may produce devastating effects and cause serious damage to the host (Crocetti et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Under normal conditions, the activity of HNE is controlled by endogenous inhibitors including secretory leukocyte proteinase inhibitor, a1-antitrypsin (a1-AT), a2macroglobulin, and elafin, but excessive and uncontrolled activity of HNE can cause serious damage to the tissues resulting in COPD, cyclic hematopoiesis, pulmonary emphysema (the loss of lungs elasticity), rheumatoid arthritis, pancreatitis, cystic fibrosis, psoriasis and bullous dermatoses, asthma, and systemic inflammatory response syndrome (Horwitz et al, 1999;Elsebai et al, 2012;Crocetti et al, 2019;Thulborn et al, 2019). HNE also localizes to Neutrophil extracellular traps (NETs) through its high DNA affinity, an unusual property for serine proteases.…”

Section: Introductionmentioning

confidence: 99%

“…Several changes resulted from elastase administration such as disorganized elastin, degradation of proteoglycans, and abnormal collagen remodeling. Regarding the dose and number of elastase challenges, many scientific groups demonstrated that mice subjected to five elastase administrations with a 1-week interval between them developed not only a more severe alveolar destruction, but also systemic manifestations, such as diaphragmatic dysfunction, weight loss, pulmonary arterial hypertension, and exercise intolerance (De et al, 2016;Crocetti et al, 2019;Giacalone et al, 2020). Thus, inhibition of elastase by chemical drugs has also been suggested as a way to recover from different inflammatory diseases.…”

Section: Introductionmentioning

confidence: 99%

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The Natural Polypeptides as Significant Elastase Inhibitors

et al. 2020

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Human neutrophil elastase (HNE) is a major cause of the destruction of tissues in cases of several different chronic andinflammatory diseases. Overexpression of the elastase enzyme plays a significant role in the pathogenesis of various diseases including chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome, rheumatoid arthritis, the rare disease cyclic hematopoiesis (or cyclic neutropenia), infections, sepsis, cystic fibrosis, myocardial ischemia/reperfusion injury and asthma, inflammation, and atherosclerosis. Human neutrophil elastase is secreted by human neutrophils due to different stimuli. Medicine-based inhibition of the over-activation of neutrophils or production and activity of elastase have been suggested to mend inflammatory diseases. Although the development of new elastase inhibitors is an essential strategy for treating the different inflammatory diseases, it has been a challenge to specifically target the activity of elastase because of its overlapping functions with those of other serine proteases. This review article highlights the reported natural polypeptides as potential inhibitors of elastase enzyme. The mechanism of action, structural features, and activity of the polypeptides have also been correlated wherever they were available.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Natural Polypeptides as Significant Elastase Inhibitors

et al. 2020

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“…The development of new and selective HNE inhibitors is of great interest, both in the academic and industrial world, for therapeutic development. Despite the discovery of numerous classes of potent HNE inhibitors (Groutas et al, 2011 ; Von Nussbaum and Li, 2015 ; Crocetti et al, 2019 ), only two drugs are currently available on the market: the peptide inhibitor Prolastin® (purified α1-antitrypsin, from Alpha Therapeutic Corp, 2003 ) and the small molecule Sivelestat. Sivelestat (ONO-5046, Figure 1 ) developed by Ono Pharmaceutical and marketed in Japan and Korea exclusively as a sodium salt in the injectable formulation Elaspol® 100 for the treatment of ARDS and ALI associated with systemic inflammatory response syndrome and in pediatric surgery to alleviate the inflammatory response induced by cardiopulmonary bypass (Kawabata et al, 1991 ; Fujii et al, 2010 ; Inoue et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Novel Sulfonamide Analogs of Sivelestat as Potent Human Neutrophil Elastase Inhibitors

et al. 2020

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Human neutrophil elastase (HNE) is involved in a number of essential physiological processes and has been identified as a potential therapeutic target for treating acute and chronic lung injury. Nevertheless, only one drug, Sivelestat, has been approved for clinical use and just in Japan and the Republic of Korea. Thus, there is an urgent need for the development of low-molecular-weight synthetic HNE inhibitors, and we have developed a wide variety of HNE inhibitors with various chemical scaffolds. We hypothesized that substitution of the active fragment of Sivelestat into these HNE inhibitor scaffolds could modulate their inhibitory activity, potentially resulting in higher efficacy and/or improved chemical stability. Here, we report the synthesis, biological evaluation, and molecular modeling studies of novel compounds substituted with the 4-(sulfamoyl)phenyl pivalate fragment necessary for Sivelestat activity. Many of these compounds were potent HNE inhibitors with activity in the nanomolar range (IC 50 = 19-30 nM for compounds 3a, 3b, 3f, 3g, and 9a), confirming that the 4-(sulfamoyl)phenyl pivalate fragment could substitute for the N-CO group at position 1 and offer a different point of attack for Ser195. Results of molecular docking of the these pivaloyl-containing compounds into the HNE binding site supported the mechanism of inhibitory activity involving a nucleophilic attack of Ser195 from the catalytic triad onto the pivaloyl carbonyl group. Furthermore, some compounds (e.g., 3a and 3f) had a relatively good stability in aqueous buffer (t 1/2 > 9 h). Thus, this novel approach led to the identification of a number of potent HNE inhibitors that could be used as leads for the further development of new therapeutics.

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“…A study focusing on NE in Bronchiectasis found that NE levels were elevated at an exacerbation state and responded to antibiotics [16]. The inhibition of NE improves lung function and airway inflammation [18], NE inhibitors and their therapeutic applications are being considered [19].…”

Section: Introductionmentioning

confidence: 99%

Neutrophil elastase as a biomarker for bacterial infection in COPD

et al. 2019

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Background Chronic obstructive pulmonary disease (COPD) is predominantly associated with neutrophilic inflammation. Active neutrophil elastase (NE) is a serine proteinase, secreted by neutrophils, in response to inflammation and pathogen invasion. We sought to investigate if NE could be used as a biomarker for bacterial infection in patients with COPD. Methods NE was quantified using ProteaseTag® Active NE Immunoassay (ProAxsis, Belfast) from the sputum of COPD subjects at stable state, exacerbation and 2 weeks post treatment visit. Results NE was measured in 90 samples from 30 COPD subjects (18 males) with a mean (range) age of 65 (45–81) years and mean (SD) FEV 1 of 47% (18). The geometric mean (95%CI) of NE at stable state was 2454 ng/mL (1460 to 4125 ng/mL). There was a significant increase in NE levels at an exacerbation ( p = 0.003), and NE levels were higher in a bacterial-associated exacerbation (NE log difference 3.873, 95% CI of log difference 1.396 to 10.740, p = 0.011). NE was an accurate predictor of a bacteria-associated exacerbation (area (95%CI) under the receiver operator characteristic curve 0.812 (0.657 to 0.968). Conclusion NE is elevated during exacerbations of COPD. NE may be a viable biomarker for distinguishing a bacterial exacerbation in patients with COPD. Trial registration Leicestershire, Northamptonshire and Rutland ethics committee (reference number: 07/H0406/157 ).

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A patenting perspective on human neutrophil elastase (HNE) inhibitors (2014-2018) and their therapeutic applications

Cited by 55 publications

References 133 publications

The Natural Polypeptides as Significant Elastase Inhibitors

The Natural Polypeptides as Significant Elastase Inhibitors

Novel Sulfonamide Analogs of Sivelestat as Potent Human Neutrophil Elastase Inhibitors

Neutrophil elastase as a biomarker for bacterial infection in COPD

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