Novel Inhibitors and Activity-Based Probes Targeting Trypsin-Like Serine Proteases

Ferguson, Timothy; Reihill, James; Martin, S. Lorraine; Walker, Brian

doi:10.3389/fchem.2022.782608

Cited by 7 publications

(11 citation statements)

References 64 publications

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“…A second-order rate constant of 2.74 × 10 6 M −1 min −1 was determined for the inactivation of trypsin by NAP830 ( Table 1 ). This is very close to the value obtained (2.06 × 10 6 M −1 min −1 ) for its exactly analogous N -alkyl arginine counterpart NAP858, against the same protease, previously reported by us ( Ferguson et al, 2022 ). This equipotency of the two ABPs was anticipated since trypsin is known to cleave peptides and proteins equally efficiently at lysine and arginine residues ( Evnin et al, 1990 ).…”

Section: Resultssupporting

confidence: 92%

“…We reported previously that NAP858 functions as an ABP for thrombin, permitting the detection of a band with an apparent molecular mass of 31 kDa, corresponding to the heavy (catalytic) chain of the protease ( Ferguson et al, 2022 ). This banding pattern is recapitulated in Figure 8B .…”

Section: Resultsmentioning

confidence: 99%

“…Previously published work from our group has demonstrated that peptide NHS-carbamates containing a P1 N -alkyl glycine mimetic of arginine are effective ABPs for trypsin-like serine proteases ( Ferguson et al, 2022 ). This present study has demonstrated that the N -alkyl glycine NHS-carbamate chemotype can be expanded to provide additional ABP examples that target a broader range of serine protease subtypes having a P1 specificity other than arginine.…”

Section: Discussionmentioning

confidence: 99%

“…As a further contribution to ABP development for the serine proteases, we have recently introduced biotinylated (NAP987) and “clickable” (NAP884) peptides containing P1 N -alkyl glycine arginine carbamates (see Figure 2 for structures) as ABPs for detection/profiling of trypsin-like serine proteases ( Ferguson et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…(D) *NAP884 and *NAP897. Structures marked with * are taken from Ferguson et al (2022) , all others are from the present study.…”

Section: Introductionmentioning

confidence: 99%

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Novel inhibitors and activity-based probes targeting serine proteases

Ferguson

Reihill²,

Martin³

et al. 2022

Front. Chem.

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Serine proteases play varied and manifold roles in important biological, physiological, and pathological processes. These include viral, bacterial, and parasitic infection, allergic sensitization, tumor invasion, and metastasis. The use of activity-based profiling has been foundational in pinpointing the precise roles of serine proteases across this myriad of processes. A broad range of serine protease-targeted activity-based probe (ABP) chemotypes have been developed and we have recently introduced biotinylated and “clickable” peptides containing P1 N-alkyl glycine arginine N-hydroxy succinimidyl (NHS) carbamates as ABPs for detection/profiling of trypsin-like serine proteases. This present study provides synthetic details for the preparation of additional examples of this ABP chemotype, which function as potent irreversible inhibitors of their respective target serine protease. We describe their use for the activity-based profiling of a broad range of serine proteases including trypsin, the trypsin-like protease plasmin, chymotrypsin, cathepsin G, and neutrophil elastase (NE), including the profiling of the latter protease in clinical samples obtained from patients with cystic fibrosis.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…(D) *NAP884 and *NAP897. Structures marked with * are taken from Ferguson et al (2022) , all others are from the present study.…”

Section: Introductionmentioning

confidence: 99%

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Novel inhibitors and activity-based probes targeting serine proteases

Ferguson

Reihill²,

Martin³

et al. 2022

Front. Chem.

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Airborne indoor allergen serine proteases and their contribution to sensitisation and activation of innate immunity in allergic airway disease

Ouyang,

Reihill,

Douglas

et al. 2024

Eur Respir Rev

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Common airborne allergens (pollen, animal dander and those from fungi and insects) are the main triggers of type I allergic disorder in the respiratory system and are associated with allergic rhinitis, allergic asthma, as well as immunoglobulin E (IgE)-mediated allergic bronchopulmonary aspergillosis. These allergens promote IgE crosslinking, vasodilation, infiltration of inflammatory cells, mucosal barrier dysfunction, extracellular matrix deposition and smooth muscle spasm, which collectively cause remodelling of the airways. Fungus and insect (house dust mite and cockroaches) indoor allergens are particularly rich in proteases. Indeed, more than 40 different types of aeroallergen proteases, which have both IgE-neutralising and tissue-destructive activities, have been documented in the Allergen Nomenclature database. Of all the inhaled protease allergens, 85% are classed as serine protease activities and include trypsin-like, chymotrypsin-like and collagenolytic serine proteases. In this article, we review and compare the allergenicity and proteolytic effect of allergen serine proteases as listed in the Allergen Nomenclature and MEROPS databases and highlight their contribution to allergic sensitisation, disruption of the epithelial barrier and activation of innate immunity in allergic airways disease. The utility of small-molecule inhibitors of allergen serine proteases as a potential treatment strategy for allergic airways disease will also be discussed.

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Preparation of novel acyl pyrazoles and triazoles by means of oxidative functionalization reactions

Wadey

Doherty

Sandoval

et al. 2023

Heterocyclic Communications

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Novel acyl pyrazoles and acyl triazoles have been prepared by means of the oxidative amidation of aldehydes in the presence of the requisite azole. Yields range from modest to good in both cases, and some limitations of the substrate scope have been discovered. Acyl pyrazoles were prepared by treatment of a mixture of aldehyde and pyrazole with an oxoammonium salt bearing the nitrate anion. In the case of acyl triazoles, the oxidative functionalization was performed using sodium persulfate as a terminal oxidant in the presence of a catalytic quantity of a nitroxide.

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Novel Inhibitors and Activity-Based Probes Targeting Trypsin-Like Serine Proteases

Cited by 7 publications

References 64 publications

Novel inhibitors and activity-based probes targeting serine proteases

Novel inhibitors and activity-based probes targeting serine proteases

Airborne indoor allergen serine proteases and their contribution to sensitisation and activation of innate immunity in allergic airway disease

Preparation of novel acyl pyrazoles and triazoles by means of oxidative functionalization reactions

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