Inhibition studies of some serine and thiol proteinases by new leupeptin analogs

McConnell, Rose M.; York, James L.; Frizzell, D; Ezell, C

doi:10.1021/jm00060a016

Cited by 67 publications

(45 citation statements)

References 10 publications

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“…As shown in Table 2, leupeptin and chymostatin inhibited C2 completely but did not inhibit TcoCBc1, which was completely resistant to both inhibitors. Furthermore, the same result was obtained with a lysinal analogue of leupeptin, acetylLeu-Val-lysinal-CHO, which reportedly is a stronger inhibitor of cathepsin B-like cysteine proteases (50). Another potent cathepsin B inhibitor belonging to the N-peptidyl, O-acyl hydroxamate family (Z-Phe-Gly-NHO-Bz-pOMe) was more active against TcoCBc1 than C2, which is in accordance with the reported data (22).…”

supporting

confidence: 88%

“…On the other hand, chymostatin, leupeptin, and its lysinal analogue, Ac-Leu-Val-Lysinal-CHO, show no or a poor inhibitory effect on the recombinant protease. These inhibitors, although not specific for cysteine proteases, strongly inhibit cathepsin B-like enzymes (22,50,58,68). These results indicate that the TcoCBc1 specificity differs from that of other known cathepsin B-like proteases.…”

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confidence: 77%

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Molecular and Biochemical Characterization of a Cathepsin B-Like Protease Family Unique toTrypanosoma congolense

et al. 2008

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Cysteine proteases have been shown to be essential virulence factors and drug targets in trypanosomatids and an attractive antidisease vaccine candidate for Trypanosoma congolense. Here, we describe an important amplification of genes encoding cathepsin B-like proteases unique to T. congolense. More than 13 different genes were identified, whereas only one or two highly homologous genes have been identified in other trypanosomatids. These proteases grouped into three evolutionary clusters: TcoCBc1 to TcoCBc5 and TcoCBc6, which possess the classical catalytic triad (Cys, His, and Asn), and TcoCBs7 to TcoCBs13, which contains an unusual catalytic site (Ser, Xaa, and Asn). Expression profiles showed that members of the TcoCBc1 to TcoCBc5 and the TcoCBs7 to TcoCBs13 groups are expressed mainly in bloodstream forms and localize in the lysosomal compartment. The expression of recombinant representatives of each group (TcoCB1, TcoCB6, and TcoCB12) as proenzymes showed that TcoCBc1 and TcoCBc6 are able to autocatalyze their maturation 21 and 31 residues, respectively, upstream of the predicted start of the catalytic domain. Both displayed a carboxydipeptidase function, while only TcoCBc1 behaved as an endopeptidase. TcoCBc1 exhibited biochemical differences regarding inhibitor sensitivity compared to that of other cathepsin B-like proteases. Recombinant proTcoCBs12 did not automature in vitro, and the pepsin-matured enzyme was inactive in tests with cathepsin B fluorogenic substrates. In vivo inhibition studies using CA074Me (a cell-permeable cathepsin B-specific inhibitor) demonstrated that TcoCB are involved in lysosomal protein degradation essential for survival in bloodstream form. Furthermore, TcoCBc1 elicited an important immune response in experimentally infected cattle. We propose this family of proteins as a potential therapeutic target and as a plausible antigen for T. congolense diagnosis.

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confidence: 88%

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confidence: 77%

Molecular and Biochemical Characterization of a Cathepsin B-Like Protease Family Unique toTrypanosoma congolense

et al. 2008

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“…Furthermore, several di-and tripeptidyl aldehyde inhibitors were synthesized and their inhibitory effects investigated toward cysteine proteases including cathepsins B and L [1]. Among these, the most potent inhibitors were reported to be acetyl-Leu-Val-lysinal toward cathepsins B (IC 50 , 4 nM) [22] and acetyl-Leu-Leunorleucinal toward cathepsin L (K i , 0.5 nM) [23], respectively. Thus, several of the present peptide aldehydes appear to possess inhibitory potencies toward cathepsins B and L comparable with or somewhat weaker than those inhibitors.…”

Section: Resultsmentioning

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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“…The most plausible explanation for this inhibitory effect of ϩ apoptotic cytosol on cathepsins from 0 necrotic cytosol is that the small peptides produced by cleavage of intracellular caspase-3 target proteins work as the cathepsin inhibitors. In fact, there are several proteins, such as Fodrin, DNA-dependent protein kinase catalytic subunit, protein kinase C, and plasma membrane calcium-transporting ATPase 4, which have both target sequences for caspase-3 cleavage (DEVD/ DEID) and inhibitory sequences for cathepsin B (LVK) (29). However, identification of every one of these peptides is extremely laborious and remains as a future task.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis Supercedes Necrosis in Mitochondrial DNA-Depleted Jurkat Cells by Cleavage of Receptor-Interacting Protein and Inhibition of Lysosomal Cathepsin

Sato

Machida

Takahashi

et al. 2008

The Journal of Immunology

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In the present study, we used mitochondrial DNA-depleted Jurkat subclones (ρ0 cells) to demonstrate that Fas agonistic Ab (CH-11), at the concentrations that evoke apoptotic death of the parental Jurkat cells, induced necrosis mainly through generation of excess reactive oxygen species, lysosomal rupture, and sequential activation of cathepsins B and D, and in minor part through activation of receptor-interacting protein (RIP). In the ρ0 cells treated with CH-11, ATP supplementation converted necrosis into apoptosis by the formation of the apoptosome and subsequent activation of procaspase-3. In these ATP-supplemented ρ0 cells (ATP-ρ0), generation of excess ROS and lysosomal rupture were still seen, yet cathepsins B and D were inactivated and RIP was degraded. The conversion of necrosis to apoptosis, RIP degradation, and cathepsin inactivation in ATP- ρ0 cells were blocked by caspase-3 inhibitors. Activities of cathepsins B and D in the lysate of necrotic ρ0 cells were inhibited by the addition of apoptotic parental Jurkat cell lysate. Thus, apoptosis may supercede necrosis.

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Inhibition studies of some serine and thiol proteinases by new leupeptin analogs

Cited by 67 publications

References 10 publications

Molecular and Biochemical Characterization of a Cathepsin B-Like Protease Family Unique toTrypanosoma congolense

Molecular and Biochemical Characterization of a Cathepsin B-Like Protease Family Unique toTrypanosoma congolense

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

Apoptosis Supercedes Necrosis in Mitochondrial DNA-Depleted Jurkat Cells by Cleavage of Receptor-Interacting Protein and Inhibition of Lysosomal Cathepsin

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