Cysteine Proteases and Their Inhibitors

Otto, Hans‐Hartwig; Schirmeister, Tanja

doi:10.1021/cr950025u

Cited by 720 publications

(667 citation statements)

References 485 publications

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“…It can be concluded that, as was observed for mechanism I, the inhibition of cruzain with PClK is much more favorable than the inhibition with PFK, once again in agreement with experimental studies of papain-like enzyme studies, 77 concluding the higher reactivity of a PClK in comparison with a PFK. 27,30,31 The rate limiting step of mechanism III would correspond to TS3 for both inhibitors with effective free energy barriers, computed from the stabilized THH, of 47.7 and 47.8 kcal·mol -1 for PFK and PClK, respectively. Nevertheless, as observed on the profiles, if reactants is considered as the reference state, the inhibition of cruzain with PClK is clearly more feasible than the inhibition with PFK.…”

Section: Resultsmentioning

confidence: 99%

First Quantum Mechanics/Molecular Mechanics Studies of the Inhibition Mechanism of Cruzain by Peptidyl Halomethyl Ketones

2015

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Cruzain is a primary cysteine protease expressed by the protozoan parasite Trypanosoma cruzi during Chagas disease infection, and thus, the development of inhibitors of this protein is a promising target for designing an effective therapy against the disease. In this paper, the mechanism of inhibition of cruzain by two different irreversible peptidyl halomethyl ketones (PHK) inhibitors has been studied by means of hybrid quantum mechanics/molecular mechanics−molecular dynamics (MD) simulations to obtain a complete representation of the possible free energy reaction paths. These have been traced on free energy surfaces in terms of the potential of mean force computed at AM1d/MM and DFT/MM levels of theory. An analysis of the possible reaction mechanisms of the inhibition process has been performed showing that the nucleophilic attack of an active site cysteine, Cys25, on a carbon atom of the inhibitor and the cleavage of the halogen−carbon bond take place in a single step. PClK appears to be much more favorable than PFK from a kinetic point of view. This result would be in agreement with experimental studies in other papain-like enzymes. A deeper analysis of the results suggests that the origin of the differences between PClK and PFK can be the different stabilizing interactions established between the inhibitors and the residues of the active site of the protein. Any attempt to explore the viability of the inhibition process through a stepwise mechanism involving the formation of a thiohemiketal intermediate and a three-membered sulfonium intermediate has been unsuccessful. Nevertheless, a mechanism through a protonated thiohemiketal, with participation of His159 as a proton donor, appears to be feasible despite showing higher free energy barriers. Our results suggest that PClK can be used as a starting point to develop a proper inhibitor of cruzain.

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Section: Resultsmentioning

confidence: 99%

First Quantum Mechanics/Molecular Mechanics Studies of the Inhibition Mechanism of Cruzain by Peptidyl Halomethyl Ketones

2015

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“…The crystal structure of LecA11a, 15 reveals the presence of one cysteine residue (Cys62) in the carbohydrate binding domain (Figure 1). The specific targeting of cysteine residues with electrophilic warheads is a general strategy in the search for cysteine protease inhibitors,16 but has never been addressed in carbohydrate recognition domains. To target Cys62, we designed the two diastereoisomeric galactose‐derived epoxides 2 and 3 (Figure 1) as potential covalent active site inhibitors of LecA.…”

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confidence: 99%

Covalent Lectin Inhibition and Application in Bacterial Biofilm Imaging

et al. 2017

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Biofilm formation by pathogenic bacteria is a hallmark of chronic infections. In many cases, lectins play key roles in establishing biofilms. The pathogen Pseudomonas aeruginosa often exhibiting various drug resistances employs its lectins LecA and LecB as virulence factors and biofilm building blocks. Therefore, inhibition of the function of these proteins is thought to have potential in developing “pathoblockers” preventing biofilm formation and virulence. A covalent lectin inhibitor specific to a carbohydrate binding site is described for the first time. Its application in the LecA‐specific in vitro imaging of biofilms formed by P. aeruginosa is also reported.

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“…Inhibition of rat liver cathepsins B and L by the peptide aldehyde benzyloxycarbonyl-leucyl-leucyl-leucinal and its analogues Introduction Among the low molecular weight inhibitors of cysteine proteases, most potent inhibitors are irreversible inhibitors such as certain nitriles, halomethyl ketones, acyloxymethyl ketones, vinyl sulfones, and epoxysuccinates, which covalently alkylate the active site thiol groups of the enzymes [1]. Alternatively, certain aldehyde-based inhibitors reversibly inhibit them by reacting with the active site thiol groups to form tetrahedral hemithioacetal intermediates [1].…”

mentioning

confidence: 99%

“…Alternatively, certain aldehyde-based inhibitors reversibly inhibit them by reacting with the active site thiol groups to form tetrahedral hemithioacetal intermediates [1]. Among them, benzyloxycarbonyl-leucyl-leucyl-leucinal (ZLLLal) draws special attention for its physiological effects.…”

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confidence: 99%

Inhibition of rat liver cathepsins B and L by the peptide aldehyde benzyloxycarbonyl-leucyl-leucyl-leucinal and its analogues

Itô

Watanabe

Kim

et al. 2009

Journal of Enzyme Inhibition and Medicinal Chemistry

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Cathepsins B and L belong to the papain superfamily of cysteine proteases and play important roles in various physiological and pathological processes. In the course of studies on their inhibitors, we examined the inhibitory effects of the peptide aldehyde benzyloxycarbonyl-leucyl-leucyl-leucinal (ZLLLal) and its analogues. As a result, rat liver cathepsins B and L were shown to be strongly inhibited by them. The concentration required for 50% inhibition (IC 50 ) by ZLLLal was 88 nM for cathepsin B and 163 nM for cathepsin L. Moreover, various analogues of ZLLLal, including 2-furancarbonyl-, nicotinyl-, isonicotinyl-and 4-morpholinylsuccinyl-LLLals, and some acetyl-Pro (AcP)-containing analogues, AcPLLLal and AcPPLLLal, were shown to inhibit both enzymes more strongly than ZLLLal. Among them, isonicotinyl-LLLal was most inhibitory against both cathepsins B (IC 50 , 12 nM) and L (IC 50 , 20 nM). Several of these inhibitors were indicated to be somewhat more soluble in aqueous media than ZLLLal.

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Cysteine Proteases and Their Inhibitors

Cited by 720 publications

References 485 publications

First Quantum Mechanics/Molecular Mechanics Studies of the Inhibition Mechanism of Cruzain by Peptidyl Halomethyl Ketones

First Quantum Mechanics/Molecular Mechanics Studies of the Inhibition Mechanism of Cruzain by Peptidyl Halomethyl Ketones

Covalent Lectin Inhibition and Application in Bacterial Biofilm Imaging

Inhibition of rat liver cathepsins B and L by the peptide aldehyde benzyloxycarbonyl-leucyl-leucyl-leucinal and its analogues

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