Novel Peptidyl α-Keto Amide Inhibitors of Calpains and Other Cysteine Proteases

Li, Zhaozhao; Ortega-Vilain, Anne-Cecile; Patil, Girish S.; Chu, Der-Lun; Foreman, Jennifer E.; Eveleth, David; Powers, James C.

doi:10.1021/jm950541c

Cited by 157 publications

(112 citation statements)

References 22 publications

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“…Using purified calpains, the IC 50 values of these two SJA compounds are approximately 0.1 M, in the IC 50 range (0.0057-1.8 M) for many peptidyl catalytic site-directed calpain inhibitors (Li et al, 1993(Li et al, , 1996Harriman et al, 2001). The presence of a methoxy group on the phenyl ring of SJA7019 increases its potency approximately 2-fold compared with SJA7029 using purified calpains.…”

Section: Discussionmentioning

confidence: 96%

“…For example, calpain inhibitor 1 (N-acetyl-Leu-Leu-norleucinal) is a tripeptidyl aldehyde. A series of peptide ␣-keto amide inhibitors of calpains have been reported (Li et al, 1993(Li et al, , 1996, and the properties of these inhibitors were tested using intact RPTs and a synthetic calpain substrate SLLVY-7-amino-4-methylcoumarin (Harriman et al, 2000). No clear correlation was obtained between the in vitro inhibitory constants of -or m-calpain and cytoprotection, therefore leaving the role of each calpain isozyme in acute renal cell injury undetermined (Harriman et al, 2000).…”

Section: Abbreviationsmentioning

confidence: 99%

“…No clear correlation was obtained between the in vitro inhibitory constants of -or m-calpain and cytoprotection, therefore leaving the role of each calpain isozyme in acute renal cell injury undetermined (Harriman et al, 2000). In addition, many of the catalytic site-directed peptidyl calpain inhibitors lack intracellular specificity, plasma membrane permeability, and/or potency (Li et al, 1993(Li et al, , 1996Wang et al, 1996;Mellgren, 1997;Sorimachi et al, 1997;Harriman et al, 2000). In contrast, the compound 3-(4-iodophenyl)-2-mercapto-(Z)-2-propenoic acid (PD150606) represents a nonpeptide Ca 2ϩ -binding site-directed calpain inhibitor and has been shown to block RPT cell death following exposure to diverse insults (Edelstein et al, 1996;Waters et al, 1997;Liu et al, 2001).…”

Section: Abbreviationsmentioning

confidence: 99%

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Cytoprotective Properties of Novel Nonpeptide Calpain Inhibitors in Renal Cells

Liu

Harriman

Schnellmann

2002

J Pharmacol Exp Ther

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Calpains are cytosolic, Ca 2ϩ -activated, neutral cysteine proteases. Rabbit renal proximal tubule (RPT) cells express bothand m-calpain. Although multiple calpain inhibitors protect against RPT cell death, most calpain inhibitors lack specificity, membrane permeability, and/or potency. A group of novel catalytic site-directed calpain inhibitors, including chloroacetic acid NЈ- [6,7-dichloro-4-(4-methoxy-phenyl)-3-oxo-3,4-dihydroquinoxalin-2-yl]hydrazide (SJA7019) and chloroacetic acid NЈ- (6,7-dichloro-4-phenyl-3-oxo-3,4-dihydroquinoxalin-2-yl) hydrazide (SJA7029), were identified to be potent calpain inhibitors in vitro. The goals of this study were to determine the action of these two compounds on 1) RPT calpain activity using fluorescein isothiocyanate-casein zymography, 2) antimycin Ainduced RPT extracellular 45 Ca 2ϩ influx and cell death, and 3) hypoxia/reoxygenation-induced RPT cellular dysfunction and death. The results showed that the SJA compounds inhibited RPT -and m-calpain with equal potency (approximate IC 50 , 30 M) and efficacy, and blocked antimycin A-induced extracellular Ca 2ϩ influx and cell death. In addition, SJA7029 blocked cell death and allowed the recovery of mitochondrial function and active Na ϩ transport in RPTs subjected to hypoxia/reoxygenation. In summary, the SJA compounds 1) were more potent inhibitors of calpains than catalytic site-directed peptide inhibitors in this model, 2) prevented extracellular Ca 2ϩ influx during the late phase of cell death, and 3) are true cytoprotectants and allow recovery of RPT cellular functions after injury.Calpains, cytosolic Ca 2ϩ -activated neutral cysteine proteases, are involved in a variety of cellular functions including the regulation of cytoskeletal structures, cell cycle progression, and cell spreading, adhesion, and migration. There is extensive evidence that calpains play a critical role in cell/tissue/organ injury and death, including renal proximal tubule (RPT) cell injury/death (Bronk and

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Section: Discussionmentioning

confidence: 96%

Section: Abbreviationsmentioning

confidence: 99%

Section: Abbreviationsmentioning

confidence: 99%

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Cytoprotective Properties of Novel Nonpeptide Calpain Inhibitors in Renal Cells

Liu

Harriman

Schnellmann

2002

J Pharmacol Exp Ther

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“…Z-Leu-NVa-CONH-CH 2 -2-pyridyl (compound 73) and Z-Leu-Abu-CONH-(CH 2 ) 3 -4-morpholinyl (compound 42), specific inhibitors of -calpain and m-calpain, respectively, were the kind gift of J. Powers (Georgia Institute of Technology, Atlanta) and used at 75 M (13). Pertussis toxin (PTx) was obtained from List Biological Laboratories (Campbell, CA).…”

Section: Methodsmentioning

confidence: 99%

Calpain regulates neutrophil chemotaxis

Lokuta

Nuzzi

Huttenlocher

2003

Proc. Natl. Acad. Sci. U.S.A.

127

133

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Cell polarization is required for directed cell migration. We investigated the role of the calcium-dependent protease calpain during neutrophil chemotaxis and found that calpain inhibition induced neutrophil adhesion, polarization, and rapid chemokinesis in the absence of exogenous activators. Resting neutrophils display constitutive calpain activity with -calpain being the predominant active isoform. Our findings suggest that constitutive calpain activity in resting neutrophils may function as a negative regulator of protrusion and migration. Specific inhibition of -calpain, but not m-calpain, induced neutrophil polarization and chemokinesis. In contrast to IL-8-induced chemokinesis, the chemokinesis induced by calpain inhibition was not reduced in the presence of pertussis toxin, suggesting that calpain functions downstream of G proteincoupled receptors. Further, both calpain inhibition and stimulation with IL-8 and formyl-Met-Leu-Phe (fMLP) induced an increase in Cdc42 and Rac activation. These findings are consistent with the involvement of calpain in chemotaxis pathways. Accordingly, calpain inhibition decreased neutrophil chemotaxis and directional persistence in a gradient of IL-8 and fMLP. Together, these data reveal a previously uncharacterized function for calpain in neutrophils and suggest that localized modulation of calpain activity may regulate neutrophil chemotaxis downstream of G-protein-coupled receptors. migration N eutrophils, key participants in the innate immune system, are the first responders to inflammatory stimuli such as bacterial infection or tissue injury. This rapid response is achieved by the detection of chemotactic gradients and the polarization and migration of neutrophils toward inflammatory mediators such as formyl-Met-Leu-Phe (fMLP) and IL-8. In the resting state, neutrophils are poorly adherent and exist in a spherical shape. A rapid change in cell morphology occurs in response to inflammatory stimuli such that neutrophils become polarized and migrate toward the inflammatory mediator. The mechanisms that regulate these changes in response to chemoattractants remain poorly understood.There has been recent progress in understanding how cells migrate directionally in a chemoattractant gradient. Although an even distribution of G protein-coupled chemoattractant receptors (GPCRs) has been found on the surface of cells during chemotaxis (1, 2), recent studies have demonstrated that a gradient of chemoattractant can induce an asymmetry in the localization of phosphatidylinositol phosphate (PIP 3 ) with enhancement at the leading edge of migrating neutrophil-like HL-60 cells (3), implying that GPCR activation leads to localized changes in membrane organization and recruitment of signaling intermediates. Previous studies have demonstrated that calpain activity is regulated by polyphosphoinositides (4), raising the intriguing possibility that calpain is an essential signaling intermediate downstream of chemoattractant-induced membrane lipid reorganization. In this paper, we explored th...

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“…Crystallographic data (excluding structure factors) for the structures reported in this paper have been deposited with the Cambridge Crys- 2 : The synthesis of the biotinylated bipyridine ligand Biot-bpy was achieved by mixing equimolar amounts of biotinylated ethylenediamine [46] with the mono-activated bipyridine diester [47] [48].…”

Section: Methodsmentioning

confidence: 99%

Inter‐ and Intramolecular Interactions in Some Supramolecular Photochemical Systems

Delahaye

Loosli

Liu

et al. 2005

Adv Funct Materials

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In supramolecular systems, the interaction between different units modulates their photophysical properties. a) For platinum(II) complexes with ligands that have extended systems, -stacking and direct metal-metal interactions result in the formation of excimers with characteristically red-shifted luminescence. Time-resolved emission spectra show clear evidence of dual luminescence. b) In phthalocyanines to which electron-donating tetrathiafulvalene (TTF) groups have been fused, the luminescence is strongly quenched by intramolecular electron transfer. The luminescence can be switched on by oxidation of the TTF groups. c) The luminescence of ruthenium tris-bipyridyl derivatives is strongly influenced by the environment. Linked to biotin, the luminescence quantum yield of such a complex is enhanced by 30 % upon binding to avidin. Furthermore, the binding to avidin induces a circular-dichroism signal from the -* transition of the initially racemic ruthenium tris-bipyridyl derivative

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Novel Peptidyl α-Keto Amide Inhibitors of Calpains and Other Cysteine Proteases

Cited by 157 publications

References 22 publications

Cytoprotective Properties of Novel Nonpeptide Calpain Inhibitors in Renal Cells

Cytoprotective Properties of Novel Nonpeptide Calpain Inhibitors in Renal Cells

Calpain regulates neutrophil chemotaxis

Inter‐ and Intramolecular Interactions in Some Supramolecular Photochemical Systems

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