Inactivation of cathepsin B by active site-directed disulfide exchange. Application in covalent affinity chromatography.

Evans, B.; Shaw, Elliott

doi:10.1016/s0021-9258(17)44446-2

Cited by 26 publications

(2 citation statements)

References 28 publications

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“…However, these symmetrical disulfides only react very slowly. If the leaving group is replaced by the smaller 2-pyridyl residue, much more effective inhibitors are obtained (factor 1000) . These inhibitors have applications in affinity chromatography 2,42,327,328 since blocking of the active site can be overcome with an excess of thiol.…”

Section: 212 Disulfidesmentioning

confidence: 99%

“…If the leaving group is replaced by the smaller 2-pyridyl residue, much more effective inhibitors are obtained (factor 1000). 327 These inhibitors have applications in affinity chromatography 2,42,327,328 since blocking of the active site can be overcome with an excess of thiol. These substances are also used for determination of the active-site concentration in cysteine proteases ("active-site titration") 42,328 and for detection and characterization of the residues localized at the active site ("reactivity probes").…”

Section: Unsaturated Derivativesmentioning

confidence: 99%

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Cysteine Proteases and Their Inhibitors

1997

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Section: 212 Disulfidesmentioning

confidence: 99%

Section: Unsaturated Derivativesmentioning

confidence: 99%

Cysteine Proteases and Their Inhibitors

1997

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Cysteinyl Proteinases and Their Selective Inactivation

Shaw

1990

Advances in Enzymology - And Related Areas of Molecular Biology

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Asymmetric Disulfanylbenzamides as Irreversible and Selective Inhibitors of Staphylococcus aureus Sortase A

et al. 2020

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Staphylococcus aureus is one of the most frequent causes of nosocomial and community-acquired infections, with drugresistant strains being responsible for tens of thousands of deaths per year. S. aureus sortase A inhibitors are designed to interfere with virulence determinants. We have identified disulfanylbenzamides as a new class of potent inhibitors against sortase A that act by covalent modification of the active-site cysteine. A broad series of derivatives were synthesized to derive structure-activity relationships (SAR). In vitro and in silico methods allowed the experimentally observed binding affinities and selectivities to be rationalized. The most active compounds were found to have single-digit micromolar K i values and caused up to a 66 % reduction of S. aureus fibrinogen attachment at an effective inhibitor concentration of 10 μM. This new molecule class exhibited minimal cytotoxicity, low bacterial growth inhibition and impaired sortase-mediated adherence of S. aureus cells. a 100 % � 0.5 % 93 % � 5.6 % n.i. 7 a 98 % � 0.1 % 14 % � 8.9 % 18 % � 1.1 % 7 f 60 % � 0.5 % n.i. 12 % � 3.1 % 7 g 18 % � 3.9 % n.i. 17 % � 7.7 % 7 h 69 % � 1.7 % 23 % � 11 % 13 % � 8.0 % 12 a 90 % � 0.5 % n.i. 15 % � 5.7 % n.i. = no inhibition at 20 μM compound concentration. All results include the mean value and standard deviations from triplicate measurements.

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Inactivation of cathepsin B by active site-directed disulfide exchange. Application in covalent affinity chromatography.

Cited by 26 publications

References 28 publications

Cysteine Proteases and Their Inhibitors

Cysteine Proteases and Their Inhibitors

Cysteinyl Proteinases and Their Selective Inactivation

Asymmetric Disulfanylbenzamides as Irreversible and Selective Inhibitors of Staphylococcus aureus Sortase A

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