Towards subunit-specific proteasome inhibitors: synthesis and evaluation of peptide α', β'-epoxyketones
| Autor: | Ute Splittgerber, Craig M. Crews, Mikael Elofsson, Royce Mohan, Jayhyuk Myung |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Proteasome Endopeptidase Complex
Macromolecular Substances medicine.medical_treatment Clinical Biochemistry Molecular Conformation subunit specificity Peptide Cysteine Proteinase Inhibitors Biochemistry Mice chemistry.chemical_compound Glutamates Multienzyme Complexes In vivo Drug Discovery medicine Aromatic amino acids Animals Chymotrypsin Trypsin Molecular Biology Aorta Cells Cultured Pharmacology chemistry.chemical_classification Protease General Medicine In vitro inhibitor Cysteine Endopeptidases Kinetics epoxyketone proteasome chemistry Proteasome Acetylation Drug Design Irritants Proteasome inhibitor Epoxy Compounds Molecular Medicine Cattle Indicators and Reagents Endothelium Vascular Peptides Cell Division medicine.drug |
| Zdroj: | Chemistry & Biology. 6:811-822 |
| ISSN: | 1074-5521 |
| DOI: | 10.1016/s1074-5521(99)80128-8 |
| Popis: | Background: The proteasome is a large multicatalytic protease complex (700 kDa) involved in a number of highly regulated processes. It has three major catalytic activities: a chymotrypsin-like activity, a trypsin-like activity and a post-glutamyl peptide hydrolyzing (PGPH) activity. To be useful as molecular probes, which could help dissect the cellular functions of the proteasome, inhibitors should be specific for the proteasome, active in vivo and selectively block only one of the three catalytic activities. To date, few inhibitors fulfill these requirements so we set out to make novel proteasome inhibitors that incorporate these characteristics. Results: A panel of amino-terminally acetylated peptide α',β'-epoxyketones with leucine in P1 and various aliphatic or aromatic amino acids in P2-P4 were prepared and evaluated. Most compounds selectively inhibited the chymotrypsin-like activity, while only weakly inhibiting the trypsin-like and PGPH activities. After optimization, one inhibitor, Ac-hFLFL-epoxide, was found to be more potent and selective for the inhibition of the chymotrypsin-like activity than several previously described inhibitors. This inhibitor also exhibited strong in vivo anti-inflammatory activity. Conclusions: Optimization of amino-terminally acetylated peptide α',β'-epoxyketones furnished a potent proteasome inhibitor, Ac-hFLFL-epoxide, that has an excellent selectivity for the chymotrypsin-like activity. The inhibitor also proved to be a potent antiproliferative and anti-inflammatory agent. The strong in vivo and in vitro activities suggest that this class of proteasome inhibitors could be both molecular probes and therapeutic agents. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|