Towards subunit-specific proteasome inhibitors: synthesis and evaluation of peptide α', β'-epoxyketones

Elofsson, Mikael; Splittgerber, Ute; Myung, Jayhyuk; Mohan, Royce; Crews, Craig M.

doi:10.1016/s1074-5521(99)80128-8

Cited by 146 publications

(118 citation statements)

References 44 publications

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“…Numerous studies on proteasomal substrate specificity have been carried out with peptide-based covalent inhibitors. [34][35][36][37][38][39][40] These studies highlight the importance of non-P1 interaction in defining and tuning substrate specificity. X-ray crystallography has proven very useful in the determination of the factors dictating the substrate specificity of the proteasome.…”

Section: Discussionmentioning

confidence: 89%

Simplified Synthetic TMC‐95A/B Analogues Retain the Potency of Proteasome Inhibitory Activity

et al. 2003

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The proteasome regulates diverse intracellular processes, including cell-cycle progression, antigen presentation, and inflammatory response. Selective inhibitors of the proteasome have great therapeutic potential for the treatment of cancer and inflammatory disorders. Natural cyclic peptides TMC-95A and B represent a new class of noncovalent, selective proteasome inhibitors. To explore the structure-activity relationship of this class of proteasome inhibitors, a series of TMC-95A/B analogues were prepared and analyzed. We found that the unique enamide functionality at the C-8 position of TMC-95s can be replaced with a simple allylamide. The asymmetric center at C-36 that distinguishes TMC-95A from TMC-95B but which necessitates a complicated separation of the two compounds can be eliminated. Therefore, these findings could lead to the development of more accessible simple analogues as potential therapeutic agents.

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Section: Discussionmentioning

confidence: 89%

Simplified Synthetic TMC‐95A/B Analogues Retain the Potency of Proteasome Inhibitory Activity

et al. 2003

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“…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%

“…Examples include TMC-86A (19) and B (20) 255 The facile syntheses of linear peptide α′,β′-epoxyketones has prompted the development of more potent peptide α′,β′-epoxyketones, such as YU101 (23) that was developed by the optimization of the amino acids of the P2-P4 positions to maximize its potency toward the CT-L activity. 235 While lactacystin and epoxomicin are the best known natural product inhibitors of the 20S proteasome, there have been other potent natural product proteasome inhibitors with novel structures. For example, in the course of proteasome inhibitor screening procedure, Kohno et al 257 found a series of TMC-95 (24) from the fermentation broth of Apiospora montagnei Sacc.…”

Section: B Natural Product Proteasome Inhibitorsmentioning

confidence: 99%

The ubiquitin‐proteasome pathway and proteasome inhibitors

Myung

Kim

Crews

2001

Medicinal Research Reviews

Self Cite

402

252

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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.

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“…The nitrophenol group was included at the N terminus because it has been shown to increase the potency of tripeptide vinyl sulfones for the proteasome (19). Libraries were synthesized by coupling a single amino acid in the constant position (C [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] ) and an isokinetic mixture of this same set of amino acids in a variable position (mix). All natural amino acids were used except cysteine due to its reactivity with the vinyl sulfone.…”

Section: Design and Synthesis Of Positional Scanned Libraries Of Protmentioning

confidence: 99%

“…However, several studies have now established the importance of distal amino acid residues in directing a substrate to an active site in the complex. Detailed kinetic studies using fluorogenic substrates (5) and covalent inhibitors have established the importance of both the P3 and P4 residues for subsite binding (6,7).…”

mentioning

confidence: 99%

Global analysis of proteasomal substrate specificity using positional-scanning libraries of covalent inhibitors

Nazif

Bogyo

2001

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

171

115

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The proteasome is a large protease complex consisting of multiple catalytic subunits that function simultaneously to digest protein substrates. This complexity has made deciphering the role each subunit plays in the generation of specific protein fragments difficult. Positional scanning libraries of peptide vinyl sulfones were generated in which the amino acid located directly at the site of hydrolysis (P1 residue) was held constant and sequences distal to that residue (P2, P3, and P4 positions) were varied across all natural amino acids (except cysteine and methionine). Binding information for each of the individual catalytic subunits was obtained for each library under a variety of different conditions. The resulting specificity profiles indicated that substrate positions distal to P1 are critical for directing substrates to active subunits in the complex. Furthermore, specificity profiles of IFN-␥-regulated subunits closely matched those of their noninducible counterparts, suggesting that subunit swapping may modulate substrate processing by a mechanism that does require a change in the primary sequence specificity of individual catalytic subunits in the complex. Finally, specificity profiles were used to design specific inhibitors of a single active site in the complex. These reagents can be used to further establish the role of each subunit in substrate processing by the proteasome.active-site labeling ͉ vinyl sulfones ͉ electrophiles T he proteasome is responsible for a wide range of cellular functions ranging from controlled processing of antigens to complete destruction of long-lived and misfolded proteins (1). The proteasome is also one of the most complex catabolic systems, owing to its multiple active sites, multitude of accessory proteins that regulate its function, and the dynamic nature of the assembled protease complex that results from swapping of active subunits upon stimulation by IFN-␥.The proteasome is a large barrel-shaped protein complex that is made up of ␣ and ␤ subunits. The ␤ subunits contain the active sites where amide bond hydrolysis takes place (2, 3). Of the seven eukaryotic ␤ subunits only three are believed to be enzymatic (1-3). These catalytic subunits create a proteolytic system that cleaves amide bonds adjacent to a variety of amino acids. The primary hydrolytic activities of the proteasome have been categorized based on the amino acid residues found directly adjacent to the scissile amide bond (4). However, several studies have now established the importance of distal amino acid residues in directing a substrate to an active site in the complex. Detailed kinetic studies using fluorogenic substrates (5) and covalent inhibitors have established the importance of both the P3 and P4 residues for subsite binding (6, 7).IFN-␥-induced exchange of subunits in the active complex originally was shown to result in modulation of both the activity and substrate specificity of the proteasome complex (8-12). Subunit swapping thereby serves to direct processing of a peptide substrate for do...

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Towards subunit-specific proteasome inhibitors: synthesis and evaluation of peptide α', β'-epoxyketones

Cited by 146 publications

References 44 publications

Simplified Synthetic TMC‐95A/B Analogues Retain the Potency of Proteasome Inhibitory Activity

Simplified Synthetic TMC‐95A/B Analogues Retain the Potency of Proteasome Inhibitory Activity

The ubiquitin‐proteasome pathway and proteasome inhibitors

Global analysis of proteasomal substrate specificity using positional-scanning libraries of covalent inhibitors

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