Neutrophil serine proteases

Skoreński, Marcin; Torzyk, Karolina; Sieńczyk, Marcin

doi:10.20517/rdodj.2022.21

Cited by 3 publications

(2 citation statements)

References 72 publications

(120 reference statements)

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“…The presented phosphonic-type compounds can be successfully applied as dual inhibitors of human neutrophil elastase and proteinase 3 in some chronic neutrophilic inflammatory diseases when it is required to stop the activity of both proteases [ 34 ]. The latest literature reports affirm that structures 111 and 113 can be some of the most powerful irreversible inhibitors which bind covalently to the active site of proteinase 3, with k inact /K I values of 4,105,900 [M −1 s −1 ] and 8,951,600 [M −1 s −1 ], respectively [ 35 ].…”

Section: Resultsmentioning

confidence: 99%

Targeted Library of Phosphonic-Type Inhibitors of Human Neutrophil Elastase

Torzyk-Jurowska,

Ciekot,

Winiarski

2024

Molecules

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Despite many years of research, human neutrophil elastase (HNE) still remains an area of interest for many researchers. This multifunctional representative of neutrophil serine proteases is one of the most destructive enzymes found in the human body which can degrade most of the extracellular matrix. Overexpression or dysregulation of HNE may lead to the development of several inflammatory diseases. Previously, we presented the HNE inhibitor with kinact/KI value over 2,000,000 [M−1s−1]. In order to optimize its structure, over 100 novel tripeptidyl derivatives of α-aminoalkylphosphonate diaryl esters were synthesized, and their activity toward HNE was checked. To confirm the selectivity of the resultant compounds, several of the most active were additionally checked against the two other neutrophil proteases: proteinase 3 and cathepsin G. The developed modifications allowed us to obtain a compound with significantly increased inhibitory activity against human neutrophil elastase with high selectivity toward cathepsin G, but none toward proteinase 3.

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Section: Resultsmentioning

confidence: 99%

Targeted Library of Phosphonic-Type Inhibitors of Human Neutrophil Elastase

Torzyk-Jurowska,

Ciekot,

Winiarski

2024

Molecules

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“…NSP proteins are initially synthesised as zymogens that are activated by cathepsin C (CTSC) via the modification of the N-terminal region of the proteins [48]. NSPs can act both intracellularly, where they degrade phagocytosed material and microorganisms, and extracellularly, where they are secreted during degranulation, and can contribute to extracellular matrix (ECM) remodelling by cleaving components, such as elastin, collagen, fibronectin and laminin [49,50]. Within the neutrophil, NSPs potentially contribute to NETosis [35,36], though their importance in this process is not fully clear due to conflicting data [21].…”

Section: Old Players: Neutrophil Serine Proteasesmentioning

confidence: 99%

Neutrophil-Derived Proteases in Lung Inflammation: Old Players and New Prospects

Cheetham,

McKelvey,

McAuley

et al. 2024

IJMS

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Neutrophil-derived proteases are critical to the pathology of many inflammatory lung diseases, both chronic and acute. These abundant enzymes play roles in key neutrophil functions, such as neutrophil extracellular trap formation and reactive oxygen species release. They may also be released, inducing tissue damage and loss of tissue function. Historically, the neutrophil serine proteases (NSPs) have been the main subject of neutrophil protease research. Despite highly promising cell-based and animal model work, clinical trials involving the inhibition of NSPs have shown mixed results in lung disease patients. As such, the cutting edge of neutrophil-derived protease research has shifted to proteases that have had little-to-no research in neutrophils to date. These include the cysteine and serine cathepsins, the metzincins and the calpains, among others. This review aims to outline the previous work carried out on NSPs, including the shortcomings of some of the inhibitor-orientated clinical trials. Our growing understanding of other proteases involved in neutrophil function and neutrophilic lung inflammation will then be discussed. Additionally, the potential of targeting these more obscure neutrophil proteases will be highlighted, as they may represent new targets for inhibitor-based treatments of neutrophil-mediated lung inflammation.

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Covalent activity-based probes for imaging of serine proteases

Skorenski,

Ji,

Verhelst

2024

Biochemical Society Transactions

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Serine proteases are one of the largest mechanistic classes of proteases. They regulate a plethora of biochemical pathways inside and outside the cell. Aberrant serine protease activity leads to a wide variety of human diseases. Reagents to visualize these activities can be used to gain insight into the biological roles of serine proteases. Moreover, they may find future use for the detection of serine proteases as biomarkers. In this review, we discuss small molecule tools to image serine protease activity. Specifically, we outline different covalent activity-based probes and their selectivity against various serine protease targets. We also describe their application in several imaging methods.

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Neutrophil serine proteases

Cited by 3 publications

References 72 publications

Targeted Library of Phosphonic-Type Inhibitors of Human Neutrophil Elastase

Targeted Library of Phosphonic-Type Inhibitors of Human Neutrophil Elastase

Neutrophil-Derived Proteases in Lung Inflammation: Old Players and New Prospects

Covalent activity-based probes for imaging of serine proteases

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