Abstract
The 20S proteasome is a multicatalytic protease complex responsible for the degradation of many proteins in mammalian cells. Specific inhibition of proteasome enzymatic subunits represents a topic of great interest for the development of new drug therapies. Following our previous development of a new class of peptide-based inhibitors bearing a C-terminal vinyl ester residue as a pharmacophoric unit that are able to interact with the catalytic threonine, we report here the synthesis and biological properties of a new series of vinyl ester cyclopeptide analogues. Some of these derivatives were shown to inhibit the chymotrypsin-like activity of the proteasome at nanomolar concentration and their potency was found to depend on the size of the tetrapeptidic cyclic portion.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Chromatography, High Pressure Liquid
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Chymotrypsin / metabolism
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Cyclization
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Endopeptidases / metabolism
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Esters / chemistry*
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Humans
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Magnetic Resonance Spectroscopy
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Models, Chemical
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Molecular Structure
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Peptides, Cyclic / chemical synthesis*
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Peptides, Cyclic / chemistry
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Peptides, Cyclic / pharmacology
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology*
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Proteasome Inhibitors*
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Protein Conformation
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Spectrometry, Mass, Electrospray Ionization
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Trypsin / metabolism
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Vinyl Compounds / chemical synthesis*
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Vinyl Compounds / chemistry
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Vinyl Compounds / pharmacology
Substances
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Esters
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Peptides, Cyclic
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Protease Inhibitors
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Proteasome Inhibitors
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Vinyl Compounds
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Endopeptidases
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Chymotrypsin
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Trypsin
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peptidylglutamylpeptide hydrolase