Irreversible Inhibitors of Serine, Cysteine, and Threonine Proteases

Powers, James C.; Asgian, Juliana L.; Ekici, Özlem Doğan; James, Karen E.

doi:10.1021/cr010182v

Cited by 965 publications

(769 citation statements)

References 753 publications

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“…Vinyl sulfones are thought to irreversibly alkylate cysteine proteases via a Michael addition followed by protonation of the α-carbon by the active site histidine to form a covalent thioether adduct (Figure 5a). 19 Two potential reasons for the reversibility of vinyl sulfone 38 are therefore either that the active site cysteine is not adding into the vinyl sulfone or that the active site histidine is not properly oriented for protonating the resulting anion. We postulated that a β-chloro vinyl sulfone could distinguish between these possibilities because cysteine protease inactivation could be accomplished via Michael addition followed by β-elimination of chloride ion thereby eliminating the need for anion protonation (Figure 5b).…”

Section: Conversion Of Substrates Into Inhibitorsmentioning

confidence: 99%

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Identification of a New Class of Nonpeptidic Inhibitors of Cruzain

et al. 2008

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Cruzain is the major cysteine protease of T. cruzi, which is the causative agent of Chagas' disease and is a promising target for the development of new chemotherapy. With the goal of developing potent nonpeptidic inhibitors of cruzain, the Substrate Activity Screening (SAS) method was used to screen a library of protease substrates initially designed to target the homologous human protease cathepsin S. Structure-based design was next used to further improve substrate cleavage efficiency by introducing additional binding interactions in the S3 pocket of cruzain. The optimized substrates were then converted to inhibitors by the introduction of cysteine protease mechanism-based pharmacophores. Inhibitor 38 was determined to be reversible even though it incorporated the vinyl sulfone pharmacophore that is well documented to give irreversible cruzain inhibition for peptidic inhibitors. The previously unexplored β-chloro vinyl sulfone pharmacophore provided mechanistic insight that led to the development of potent irreversible acyl-and aryl-oxymethyl ketone cruzain inhibitors. For these inhibitors, potency did not solely depend on leaving group pK a , with 2,3,5,6-tetrafluorophenoxymethyl ketone 54 identified as one of the most potent inhibitors with a second order inactivation constant of 147,000 s −1 M −1 . This inhibitor completely eradicated the T. cruzi parasite from mammalian cell cultures and consequently has the potential to lead to new chemotherapeutics for Chagas' disease.

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Section: Conversion Of Substrates Into Inhibitorsmentioning

confidence: 99%

“…21,22 This pharmacophore has led to potent time-dependent inhibitors of cathepsins B, L, and S. 19 Hence, we next incorporated the acyloxymethyl ketone pharmacophore. The synthesis of the acyloxymethyl ketone inhibitors required the preparation of azide intermediates 47a and 47b (Scheme 5).…”

Section: Conversion Of Substrates Into Inhibitorsmentioning

confidence: 99%

Identification of a New Class of Nonpeptidic Inhibitors of Cruzain

et al. 2008

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“…Endopeptidases are classified according to their catalytic mechanism, which implies specificity in the enzyme active sites. In plants, four classes of endopeptidases have been described: serine proteases (SP,EC.3.4.21), cysteine proteases (CP,EC.3.4.22), aspartic proteases (AP, EC.3.4.23) and metalloproteases (MP,EC.3.4.24) (Rawling and Barrett 1994;Powers et al 2002). For SP and CP, the hydroxyl or sulfhydryl groups of the active-site amino acids act as the nucleophile during catalysis.…”

Section: Introductionmentioning

confidence: 99%

Proteolytic activities in Phaseolus vulgaris cotyledons under copper stress

Karmous

Khadija

Chaoui

et al. 2012

Physiol Mol Biol Plants

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The changes in the protease activities of bean cotyledons were investigated in response to copper stress. Assays using synthetic substrates and specific protease inhibitors followed by activity measurements and electrophoresis analysis allowed to study the classes of enzymes involved in the storage protein mobilization during the germination of bean (Phaseolus vulgaris L) seeds, and then identify which ones were affected in the presence of 200 μM CuCl 2 in the imbibition medium. Copper treatment affected embryo growth and total protease activity. The results of SDS-gelatin-PAGE show that Cu excess led to a decrease in protease activity of 45 to 66 kDa. Moreover, cysteine-, aspartic-and metallo-protease activities were markedly lowered under copper stress, while serine-protease one was enhanced as well as its activity dependent abundance in comparison with control. However, the relative distribution of major cysteine protease in H 2 O-germinated seeds was significantly diminished after Cu exposure. Thus, copper excess can disturb the nitrogen freeing from reserve tissues at enzymatic level; differential responses of protease classes are discussed, notably, cysteine protease in the way of storage protein mobilization and serine protease in protective mechanism one.

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“…[1][2][3][4][5][6][7] The efficiency of β-lactams as enzyme inhibitors depends on the molecular recognition by the protein as well as on the intrinsic chemical reactivity of the β-lactam, both of which affect the rate at which these inhibitors acylate the serine residue. 8 Among the most extensively studied enzymatic reactions of β-lactams is the inhibition of class A β-lactamases by penam sulfone inhibitors such as sulbactam, 1 (Scheme 1), tazobactam and their analogues.…”

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confidence: 99%