Bifunctional inhibitors of the trypsin-like activity of eukaryotic proteasomes

Loidl, Günther; Groll, M.; Musiol, Hans-Jürgen; Ditzel, Lars; Huber, Robert; Moröder, Luis

doi:10.1016/s1074-5521(99)80036-2

Cited by 67 publications

(61 citation statements)

References 36 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: 88%

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: 88%

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

et al. 2003

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“…Synthesis of the Inhibitors. The synthesis of Ac-Leu-LeuNle-H (1) and H-Leu-Leu-Nle-semicarbazone (Sc) trifluoroacetate (23) as well as H-Val-Arg(Adoc) 2 -diethyl acetal (22) have been reported. The tripeptide aldehyde Ac-Arg-ValArg-H (2) was prepared as outlined in Scheme 1, and the polyoxyethylene (PEG)͞peptide aldehyde conjugates (7)(8)(9)(10)(11) were obtained following the synthetic routes of Scheme 2.…”

Section: Methodsmentioning

confidence: 99%

“…We previously have reported the structure-based design of bifunctional inhibitors of the proteasome that led to maleoyl-␤-Ala-Val-Arg-H as a highly specific inhibitor of the trypsinlike activity (22). In the present study an approach to proteasome inhibition is presented, where the unique arrangement of six active sites in one enzyme particle is used for the design of bivalent inhibitors (Fig.…”

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confidence: 96%

Bivalency as a principle for proteasome inhibition

Loidl

Groll

Musiol

et al. 1999

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

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The proteasome, a multicatalytic protease, is known to degrade unfolded polypeptides with low specificity in substrate selection and cleavage pattern. This lack of welldefined substrate specificities makes the design of peptidebased highly selective inhibitors extremely difficult. However, the x-ray structure of the proteasome from Saccharomyces cerevisiae reveals a unique topography of the six active sites in the inner chamber of the protease, which lends itself to strategies of specific multivalent inhibition. Structure-derived active site separation distances were exploited for the design of homo-and heterobivalent inhibitors based on peptide aldehyde head groups and polyoxyethylene as spacer element. Polyoxyethylene was chosen as a f lexible, linear, and proteasome-resistant polymer to mimic unfolded polypeptide chains and thus to allow access to the proteolytic chamber. Spacer lengths were selected that satisfy the inter-and intra-ring distances for occupation of the active sites from the S subsites. X-ray analysis of the proteasome͞bivalent inhibitor complexes confirmed independent recognition and binding of the inhibitory head groups. Their inhibitory potencies, which are by 2 orders of magnitude enhanced, compared with pegylated monovalent inhibitors, result from the bivalent binding. The principle of multivalency, ubiquitous in nature, has been successfully applied in the past to enhance affinity and avidity of ligands in molecular recognition processes. The present study confirms its utility also for inhibition of multicatalytic protease complexes.The proteasome is a multicatalytic protease complex that is involved in intracellular protein turnover in all three kingdoms of life. The proteasome is located in both the cytosol and the nucleus and acts in the degradation of abnormal, misfolded, or improperly assembled proteins, in stress response, cell cycle control, cell differentiation, metabolic adaptation, and cellular immune response. It also is involved in many pathophysiological processes like inflammation and cancer and constitutes a promising target for drug design. In mammals the proteasomes also are responsible for the production of the bulk of antigenic peptides, which are presented via MHC class I molecules on the cell surface to cytotoxic T lymphocytes. The antiviral cytokine INF-␥ induces transcription of three additional ␤ subunits (LMP2, MECL-1, and LMP7), which can replace their constitutive homologs (␤1, ␤2, and ␤5) in newly assembled proteasomes. The resulting immuno-proteasomes show altered cleavage patterns in vitro; these are thought to be essential for the proteasomal antigen processing (1). Most of these functions are linked to an ubiquitin-and ATP-dependent protein degradation pathway involving the 26S proteasome whose core and proteolytic chamber is formed by the 20S proteasome (2-7). The eukaryotic 20S proteasome consists of seven different ␣-type and seven different ␤-type subunits, all of which have been cloned and sequenced and can be grouped by sequence homology (8)....

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“…Therefore, a new generation of compounds that specifically inhibit the PGPH or T-L activities may be required to perform a careful analysis of proteasome subunit function and to gain insights into the possibility for potential therapeutic intervention. For example, Loidl et al 261 developed a T-L activity specific aldehyde inhibitor (27) by structure-based rational design and a bivalent T-L specific proteasome inhibitor (28), in which two tripeptide aldehydes were linked through a polymeric spacer that is appropriate for simultaneous binding at two active sites. 262 Another interesting but not fully understood proteasome inhibitor 4-hydroxy-2-nonenal (HNE) (29) is a major end product of lipid peroxidation (Fig.…”

Section: B Natural Product Proteasome Inhibitorsmentioning

confidence: 99%

The ubiquitin‐proteasome pathway and proteasome inhibitors

Myung

Kim

Crews

2001

Medicinal Research Reviews

395

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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Bifunctional inhibitors of the trypsin-like activity of eukaryotic proteasomes

Cited by 67 publications

References 36 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

Bivalency as a principle for proteasome inhibition

The ubiquitin‐proteasome pathway and proteasome inhibitors

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