Neutrophil elastase inhibitors

Abstract

Introduction Chronic obstructive pulmonary disease (COPD) constitutes a worldwide health problem. There is currently an urgent and unmet need for the development of small molecule therapeutics capable of blocking and/or reversing the progression of the disorder. Recent studies have greatly illuminated our understanding of the multiple pathogenic processes associated with COPD. Of paramount importance is the key role played by proteases, oxidative stress, apoptosis, and inflammation. Insights gained from these studies have made possible the exploration of new therapeutic approaches. Areas covered An overview of major developments in COPD research with emphasis on low molecular weight neutrophil elastase inhibitors is described in this review. Expert opinion Great strides have been made toward our understanding of the biochemical and cellular events associated with COPD. However, our knowledge regarding the inter-relationships among the multiple pathogenic mechanisms and their mediators involved is till limited. The problem is further compounded by the unavailability of suitable validated biomarkers for assessing the efficacy of potential therapeutic interventions. The complexity of COPD suggests that effective therapeutic interventions may require the administration of more than one agent such as, for instance, an HNE or MMP-12 inhibitor with an anti-inflammatory agent such as a phosphodiesterase-4 inhibitor, or a dual function agent capable of disrupting the cycle of proteolysis, apoptosis, inflammation and oxidative stress

Emerging anti-inflammatory strategies for COPD

“…Although irreversible inhibitors have been shown to function effectively in vivo in hamsters to reduce many of the effects of intratracheally administered NE, their toxicity prevents clinical use. Sivelestat, which is marketed in Japan and Korea for the treatment of acute lung injury associated with systemic inflammatory response syndrome, and ONO-6818 have been developed and have seen mixed results in human studies, while other NE inhibitors in preclinical or phase I trials were discontinued for various reasons [149]. Interestingly, 3 months of treatment with AZD9668 did not improve lung function, respiratory signs and symptoms or quality of life score when added to budesonide/ formoterol maintenance therapy in patients with COPD [150].…”

Neutrophil serine proteases and their endogenous inhibitors in coronary artery ectasia patients

“…In addition to participating in acute inflammatory, activated neutrophils could induce tissue damage and regulate inflammatory responses by releasing NSPs, deriving oxidative metabolism, and producing a set of pro-inflammatory (7, 30). Excessive or dysregulated neutrophil responses together with inadequate repair contributed to persisting tissue damage that underlay many chronic inflammatory diseases, including rheumatoid arthritis, pulmonary emphysema, asthma, and so on (9-11, 21).…”

Asn347 Glycosylation of Corticosteroid-binding Globulin Fine-tunes the Host Immune Response by Modulating Proteolysis by Pseudomonas aeruginosa and Neutrophil Elastase

“…In-gel Digestion and Isolation of CBG Peptides-Gel bands corresponding to undigested intact CBG (55-60 kDa), the large CBG-Nt fragment (50)(51)(52)(53)(54)(55), and the small CBG-Ct fragment (5-10 kDa) were excised from the gels, diced, and washed with 100 mM NH 4 HCO 3 (aqueous) and 50% (v/v) acetonitrile. In-gel digestion was performed using modified porcine trypsin (Promega) (100 ng/gel band) overnight in 50 mM NH 4 HCO 3 (aqueous), pH 6.8, at 37°C.…”