Clarification of Mechanism of Human Sputum Elastase Inhibition by a New Inhibitor, ONO-5046, Using Electrospray Ionization Mass Spectrometry

Nakayama, Y.; Odagaki, Yoshihiko; Fujita, Setsuko; Matsuoka, Shozo; Hamanaka, Nobuyuki; Nakai, Hisao; Toda, Masaaki

doi:10.1016/s0960-894x(02)00393-1

Cited by 32 publications

(34 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sivelestat (Figure 1) has a distinct mechanism from compound 1 ; it acylates the active site Ser residue of elastase with a pivalyl moiety. 53 This binding is chemically reversible, regenerating the active elastase after deacylation.…”

Section: Discussionmentioning

confidence: 99%

Potent Elastase Inhibitors from Cyanobacteria: Structural Basis and Mechanisms Mediating Cytoprotective and Anti-Inflammatory Effects in Bronchial Epithelial Cells

et al. 2013

View full text Add to dashboard Cite

We discovered new structural diversity to a prevalent, yet medicinally underappreciated, cyanobacterial protease inhibitor scaffold and undertook comprehensive protease profiling to reveal potent and selective elastase inhibition. SAR and X-ray cocrystal structure analysis allowed a detailed assessment of critical and tunable structural elements. To realize the therapeutic potential of these cyclodepsipeptides, we probed the cellular effects of a novel and representative family member, symplostatin 5 (1), which attenuated the downstream cellular effects of elastase in an epithelial lung airway model system, alleviating clinical hallmarks of chronic pulmonary diseases such as cell death, cell detachment and inflammation. This compound attenuated the effects of elastase on receptor activation, proteolytic processing of the adhesion protein ICAM-1, NF-κB activation and transcriptomic changes, including the expression of pro-inflammatory cytokines IL1A, IL1B and IL8. Compound 1 exhibited activity comparable to the clinically-approved elastase inhibitor sivelestat in short-term assays and demonstrated superior sustained activity in longer-term assays.

show abstract

Section: Discussionmentioning

confidence: 99%

Potent Elastase Inhibitors from Cyanobacteria: Structural Basis and Mechanisms Mediating Cytoprotective and Anti-Inflammatory Effects in Bronchial Epithelial Cells

et al. 2013

View full text Add to dashboard Cite

show abstract

“…47,48 NE inhibition by ␣ 1 -AT is irreversible, whereas ONO-5046 inhibits NE activity reversibly. 49 Therefore, it might be reasonable to discuss that ␣ 1 -AT traps NE immediately and irreversibly in the injured lung, and ONO-5046 inhibited the excess NE that escaped from the natural defense system of ␣ 1 -AT. In the situation that BNx induces NE production, ONO-5046 may not influence on the NE-␣ 1 -AT complex formation and clearance.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil Elastase Contributes to Acute Lung Injury Induced by Bilateral Nephrectomy

Ishii

Doi

Okamoto

et al. 2010

The American Journal of Pathology

View full text Add to dashboard Cite

Acute kidney injury (AKI) is a serious problem in critically ill patients of intensive care units. It has been reported previously that AKI can induce acute lung injury (ALI), as well as cause injuries to other remote organs , including the lungs. Patients with AKI complicated by ALI show remarkably high mortality. ALI is characterized by neutrophil infiltration into the lung. Neutrophil elastase (NE) is a key enzyme for tissue injury caused by activated neutrophils , such as occurs in ALI. Therefore , this study investigated the role of NE in AKI-induced ALI using a specific NE inhibitor , sivelestat sodium hydrate (ONO-5046), in a mouse bilateral nephrectomy model. Bilateral nephrectomy showed not only a remarkable increase in blood urea nitrogen levels, but also demonstrated neutrophil infiltration into the lung, increased pulmonary inflammatory cytokine expression [interleukin-6, neutrophil chemokine keratinocyte-derived chemokine, and tumor necrosis factor-␣], and protein leakage with early increases in both systemic and pulmonary NE activity. ONO-5046 treatment reduced NE activity and improved these pulmonary inflammatory responses. Additionally, ONO-5046-treated animals had longer survival times. These data demonstrate that increasing NE activity induces pulmonary inflammatory damage in a bilateral nephrectomy model. Blockade of NE activity will be a useful therapeutic strategy for ALI complications in AKI patients. Acute lung injury (ALI) is a life-threatening condition that is frequently complicated with acute kidney injury (AKI), which is a serious condition in intensive care units. The ALI mortality is higher than 50% and increases with the development of other organ failure including AKI.1 One report described a mortality rate higher than 80% for patients with AKI complicated with ALI.2 Current prevention and treatment strategies for AKI cannot sufficiently improve the mortality of these severely ill patients. Although many basic and clinical researchers are investigating novel therapies for AKI, 3 targeting of other organ damages caused by AKI is also necessary for improving AKI outcomes.Recently, it has been suggested that AKI influences other remote organs including the lungs.4 -6 Experimental evidence indicates that AKI-induced ALI occurs not only by volume overload, but also through deleterious kidneylung interactions. Mechanisms of AKI-induced ALI include dysregulation of inflammatory reaction, innate immune response, oxidative stress, apoptosis, and soluble mediator metabolism.7 Rodent models of bilateral nephrectomy (BNx) and renal ischemia reperfusion have been used to investigate the role of AKI in the pathogenesis of ALI. 8 -11 Ischemic AKI engenders increased pulmonary vascular permeability by down-regulating pulmonary epithelial sodium channel, Na,K-ATPase, and aquaporin-5. 10 Ischemic AKI induced leukocyte accumulation and activation of inflammatory transcription factors such as nuclear factor-B and p38 mitogen-activated protein kinase in the lung, which was attenuated by an anti-infla...

show abstract

“…The HNE acylating agent par excellence continues to be Sivelestat (Elaspol R ) (Figure 4) (89), marketed in Japan and Korea for the treatment of acute lung injury associated with systemic inflammatory response syndrome and is currently explored for a range of other indications, including sepsis associated with acute respiratory distress syndrome and disseminated intravascular coagulation (90–92). …”

Section: Hne Inhibitorsmentioning

confidence: 99%

Neutrophil elastase inhibitors

Groutas

Dou

Alliston

2011

Expert Opinion on Therapeutic Patents

View full text Add to dashboard Cite

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

show abstract

Clarification of Mechanism of Human Sputum Elastase Inhibition by a New Inhibitor, ONO-5046, Using Electrospray Ionization Mass Spectrometry

Cited by 32 publications

References 9 publications

Potent Elastase Inhibitors from Cyanobacteria: Structural Basis and Mechanisms Mediating Cytoprotective and Anti-Inflammatory Effects in Bronchial Epithelial Cells

Potent Elastase Inhibitors from Cyanobacteria: Structural Basis and Mechanisms Mediating Cytoprotective and Anti-Inflammatory Effects in Bronchial Epithelial Cells

Neutrophil Elastase Contributes to Acute Lung Injury Induced by Bilateral Nephrectomy

Neutrophil elastase inhibitors

Contact Info

Product

Resources

About