Serine Proteases and Their Inhibitors in Human Health and Disease

Rachel, K. Vijaya; Sirisha, Gandreddi V. D.

doi:10.1007/978-981-10-3162-5_10

Cited by 4 publications

(3 citation statements)

References 120 publications

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“…Furthermore, it is a component of neutrophil extracellular traps (NETs), a network of chromatin and granular proteins that is secreted by neutrophils to trap and kill pathogens . Chymase is linked to atherosclerosis and gastric cancer, and numerous other serine proteases are involved in carcinogenesis, tumor progression, and neurodegeneration . Hence, serine proteases are attractive drug targets and protease inhibitors represent promising drug candidates.…”

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confidence: 99%

“…4 Chymase is linked to atherosclerosis and gastric cancer, and numerous other serine proteases are involved in carcinogenesis, tumor progression, and neurodegeneration. 5 Hence, serine proteases are attractive drug targets and protease inhibitors represent promising drug candidates. For example, camostat is an approved drug for treatment of chronic pancreatitis.…”

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confidence: 99%

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Facile Synthesis of Aminomethyl Phosphinate Esters as Serine Protease Inhibitors with Primed Site Interaction

Kähler

Lenders

Plassche

et al. 2020

ACS Med. Chem. Lett.

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Serine proteases comprise about one-third of all proteases, and defective regulation of serine proteases is involved in numerous diseases. Therefore, serine protease inhibitors are promising drug candidates. Aminomethyl diphenyl phosphonates have been regularly used as scaffolds for covalent serine protease inhibition and the design of activity-based probes. However, they cannot make use of a protease's primed site. Therefore, we developed a facile two-step synthesis toward a set of phenyl phosphinates, which is a related scaffold but can interact with the primed site. We tested their inhibitory activity on five different serine proteases and found that a phenyl group directly attached to the phosphorus atom leads to superior activity compared with phosphonates.

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confidence: 99%

mentioning

confidence: 99%

Facile Synthesis of Aminomethyl Phosphinate Esters as Serine Protease Inhibitors with Primed Site Interaction

Kähler

Lenders

Plassche

et al. 2020

ACS Med. Chem. Lett.

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“…A growing number of studies suggest a significant role of chymase in accounting for Ang II formation in human cardiovascular tissue and the consequent pathological remodeling associated with increased RAS activity [5,28-30]. Serine proteases and their inhibitors are being extensively studied in various diseased conditions like inflammation, cancer, skin diseases, atherosclerosis, immunological disorders and other pathologies [31,32]. In this review, we will document in detail the specific role of MC serine protease (chymase) including the new concept of RAS pathways in the development and progression of various cardiac diseases.…”

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confidence: 99%

Chymase inhibitors for the treatment of cardiac diseases: a patent review (2010–2018)

Ahmad

Ferrario

2018

Expert Opinion on Therapeutic Patents

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Introduction: Chymase is primarily found in mast cells (MCs), fibroblasts, and vascular endothelial cells. MC chymase is released into the extracellular interstitium in response to inflammatory signals, tissue injury, and cellular stress. Among many functions, chymase is a major extravascular source for angiotensin II (Ang II) generation. Several recent pre-clinical and a few clinical studies point to the relatively unrecognized fact that chymase inhibition may have significant therapeutic advantages over other treatments in halting progression of cardiac and vascular disease. Area covered: The present review covers patent literature on chymase inhibitors for the treatment of cardiac diseases registered between 2010 and 2018. Expert opinion: Increase in cardiac MC number in various cardiac diseases has been found in pathological tissues of human and experimental animals. Meta-analysis data from large clinical trials employing angiotensin converting enzyme (ACE) inhibitors show a relatively small risk reduction of clinical cardiovascular endpoints. The disconnect between the expected benefit associated with Ang II blockade of synthesis or activity underscore a greater participation of chymase compared to ACE in forming Ang II in humans. Emerging literature and a reconsideration of previous studies provide lucid arguments to reconsider chymase as a primary Ang II forming enzyme in human heart and vasculature.

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DON/DRP‐104 as potent serine protease inhibitors implicated in SARS‐CoV‐2 infection: Comparative binding modes with human TMPRSS2 and novel therapeutic approach

Oduro‐Kwateng,

Soliman

2024

J of Cellular Biochemistry

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Human transmembrane serine protease 2 (TMPRSS2) is an important member of the type 2 transmembrane serine protease (TTSP) family with significant therapeutic markings. The search for potent TMPRSS2 inhibitors against severe acute respiratory syndrome coronavirus 2 infection with favorable tissue specificity and off‐site toxicity profiles remains limited. Therefore, probing the anti‐TMPRSS2 potential of enhanced drug delivery systems, such as nanotechnology and prodrug systems, has become compelling. We report the first in silico study of TMPRSS2 against a prodrug, [isopropyl(S)‐2‐((S)‐2‐acetamido‐3‐(1H‐indol‐3‐yl)‐propanamido)‐6‐diazo‐5‐oxo‐hexanoate] also known as DRP‐104 synthesized from 6‐Diazo‐5‐oxo‐l‐norleucine (DON). We performed comparative studies on DON and DRP‐104 against a clinically potent TMPRSS2 inhibitor, nafamostat, and a standard serine protease inhibitor, 4‐(2‐Aminoethyl) benzenesulfonyl fluoride (AEBSF) against TMPRSS2 and found improved TMPRSS2 inhibition through synergistic binding of the S1/S1' subdomains. Both DON and DRP‐104 had better thermodynamic profiles than AEBSF and nafamostat. DON was found to confer structural stability with strong positive correlated inter‐residue motions, whereas DRP‐104 was found to confer kinetic stability with restricted residue displacements and reduced loop flexibility. Interestingly, the Scavenger Receptor Cysteine‐Rich (SRCR) domain of TMPRSS2 may be involved in its inhibition mechanics. Two previously unidentified loops, designated X (270−275) and Y (293−296) underwent minimal and major structural transitions, respectively. In addition, residues 273−277 consistently transitioned to a turn conformation in all ligated systems, whereas unique transitions were identified for other transitioning residue groups in each TMPRSS2‐inhibitor complex. Intriguingly, while both DON and DRP‐104 showed similar loop transition patterns, DRP‐104 preserved loop structural integrity. As evident from our systematic comparative study using experimentally/clinically validated inhibitors, DRP‐104 may serve as a potent and novel TMPRSS2 inhibitor and warrants further clinical investigation.

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Serine Proteases and Their Inhibitors in Human Health and Disease

Cited by 4 publications

References 120 publications

Facile Synthesis of Aminomethyl Phosphinate Esters as Serine Protease Inhibitors with Primed Site Interaction

Facile Synthesis of Aminomethyl Phosphinate Esters as Serine Protease Inhibitors with Primed Site Interaction

Chymase inhibitors for the treatment of cardiac diseases: a patent review (2010–2018)

DON/DRP‐104 as potent serine protease inhibitors implicated in SARS‐CoV‐2 infection: Comparative binding modes with human TMPRSS2 and novel therapeutic approach

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