Inhibitors of the chymotrypsin-like activity of proteasome based on di- and tri-peptidyl α-keto aldehydes (glyoxals)

Lynas, John F.; Harriott, Patrick; Healy, Adrienne; McKervey, M. Anthony; Walker, Brian

doi:10.1016/s0960-894x(98)00030-4

Cited by 66 publications

(51 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It should be noted that, for other class of proteasome inhibitors, at least three amino acid chains are required to moderately inhibit the proteasomal activity. 223,228,235 The most well characterized compound of this class is a dipeptide boronic acid PS-341 (14). 234,236 Analogous to many other proteasome inhibitors that block cell cycle progression, PS-341 treatment also results in accumulation of cells in the G 2 -M phase, 237 eventually leading to apoptosis after prolonged treatments of cells.…”

Section: A Synthetic Proteasome Inhibitorsmentioning

confidence: 99%

The ubiquitin‐proteasome pathway and proteasome inhibitors

Myung

Kim

Crews

2001

Medicinal Research Reviews

402

252

View full text Add to dashboard Cite

The ubiquitin-proteasome pathway has emerged as a central player in the regulation of several diverse cellular processes. Here, we describe the important components of this complex biochemical machinery as well as several important cellular substrates targeted by this pathway and examples of human diseases resulting from defects in various components of the ubiquitin-proteasome pathway. In addition, this review covers the chemistry of synthetic and natural proteasome inhibitors, emphasizing their mode of actions toward the 20S proteasome. Given the importance of proteasomemediated protein degradation in various intracellular processes, inhibitors of this pathway will continue to serve as both molecular probes of major cellular networks as well as potential therapeutic agents for various human diseases.

show abstract

Section: A Synthetic Proteasome Inhibitorsmentioning

confidence: 99%

The ubiquitin‐proteasome pathway and proteasome inhibitors

Myung

Kim

Crews

2001

Medicinal Research Reviews

402

252

View full text Add to dashboard Cite

show abstract

“…The cytokines were purchased from R&D Systems (Abingdon, UK). The synthetic peptidyl alpha-keto aldehyde proteasome inhibitor was synthesized on an ABI/Pioneer automated peptide synthesizer (Lynas et al 1998).…”

Section: Materials and Reagentsmentioning

confidence: 99%

High glucose decreases intracellular glutathione concentrations and upregulates inducible nitric oxide synthase gene expression in intestinal epithelial cells

Powell¹,

Warpeha²,

Xu³

et al. 2004

Journal of Molecular Endocrinology

Self Cite

View full text Add to dashboard Cite

Diabetes is associated with oxidative stress and increased concentrations of inflammatory cytokines. The aim of the study was to assess the effects of inflammatory cytokines and oxidative stress associated with increased glucose concentrations on inducible nitric oxide synthase (iNOS) promoter activity in intestinal epithelial cells. High-glucose (25 mmol/l) conditions reduced glutathione (GSH) concentrations in the human intestinal epithelial cell line, DLD-1. Addition of the antioxidant, α-lipoic acid, resulted in the restoration of GSH concentrations to normal. Upregulation of basal iNOS promoter activity was observed when cells were incubated in high glucose alone. This effect was significantly reduced by the addition of the antioxidant, α-lipoic acid, and completely blocked with inhibition of nuclear factor kappa B (NFκB) activity. Stimulation of cytokines (interleukin-1 beta, tumour necrosis factor-alpha, interferon-gamma) induced iNOS promoter activity in all conditions and this was accompanied by an increase in nitric oxide (NO) production. Inhibition of NFκB activity decreased, but did not completely inhibit, cytokine-induced iNOS promoter activity and subsequent production of NO. In conclusion, iNOS promoter activity induced by high concentrations of glucose is mediated in part through intracellular GSH and NFκB.

show abstract

“…The specificity of the peptidyl a-keto aldehyde proteasome inhibitor BzLLLCOCHO (13) and proteasome inhibitors PS-341 and MG-132 on individual proteolytic activities was investigated using conventional fluorogenic substrates. In addition, we used a novel active site-directed probe to label catalytic subunits of both the constitutive and immunoproteasome (14). Differential subunit specificities were found for each of the inhibitors toward subunits of the constitutive and immunoproteasome.…”

Section: Introductionmentioning

confidence: 99%

Comparative Selectivity and Specificity of the Proteasome Inhibitors BzLLLCOCHO, PS-341, and MG-132

Crawford¹,

et al. 2006

Self Cite

View full text Add to dashboard Cite

The 26S proteasome is a multicatalytic protease responsible for regulated intracellular protein degradation. Its function is mediated by three main catalytic activities: (a) chymotrypsinlike (CT-L), (b) trypsin-like, and (c) peptidylglutamyl peptide hydrolysing (PGPH). Proteasome inhibition is an emerging therapy for many cancers and is a novel treatment for multiple myeloma. Here, we profile the contributions of the three catalytic activities in multiple myeloma cell lines and compare the specificity and cytotoxicity of the novel proteasome inhibitor BzLLLCOCHO and inhibitors PS-341 (Velcade, bortezomib) and MG-132. Using fluorogenic substrates and an active site-directed probe specific for proteasome catalytic subunits, we show differential subunit specificity for each of the inhibitors. Addition of BzLLLCOCHO strongly inhibited all three catalytic activities, treatment with PS-341 completely inhibited CT-L and PGPH activities, and treatment with MG-132 resulted in weak inhibition of the CT-L and PGPH activities. Multiple myeloma cells were more sensitive to induction of apoptosis by PS-341 and MG-132 than BzLLLCO-CHO. This study emphasizes the need for further investigation of the effects of these compounds on gene and protein expression in the cell to allow for the development of more specific and targeted inhibitors. (Cancer Res 2006; 66(12): 6379-86)

show abstract

Inhibitors of the chymotrypsin-like activity of proteasome based on di- and tri-peptidyl α-keto aldehydes (glyoxals)

Cited by 66 publications

References 20 publications

The ubiquitin‐proteasome pathway and proteasome inhibitors

The ubiquitin‐proteasome pathway and proteasome inhibitors

High glucose decreases intracellular glutathione concentrations and upregulates inducible nitric oxide synthase gene expression in intestinal epithelial cells

Comparative Selectivity and Specificity of the Proteasome Inhibitors BzLLLCOCHO, PS-341, and MG-132

Contact Info

Product

Resources

About