Abstract
The 26S proteasome is a multicatalytic protease complex that plays an essential role in intracellular protein degradation. We have synthesized and tested a series of arecoline peptide derivatives where the peptide portion derives from a screening of tripeptide sequences, and the arecoline moiety has been considered as a potential substrate for catalytic threonine. Derivatives 17-19 are the best compounds of the series, showing chymotryptic-like (beta5) inhibition (IC(50) congruent with 1 microM) and favorable pharmacokinetic properties.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Arecoline / analogs & derivatives*
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Arecoline / chemical synthesis*
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Arecoline / pharmacology
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Cysteine Endopeptidases / blood
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Cysteine Endopeptidases / chemistry
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Cysteine Endopeptidases / metabolism*
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Cysteine Proteinase Inhibitors / chemical synthesis
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Cysteine Proteinase Inhibitors / pharmacology
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Drug Stability
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology
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Humans
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Multienzyme Complexes / blood
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Multienzyme Complexes / chemistry
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Multienzyme Complexes / metabolism*
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Oligopeptides / chemical synthesis*
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Oligopeptides / pharmacology
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Proteasome Endopeptidase Complex
Substances
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Cysteine Proteinase Inhibitors
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Enzyme Inhibitors
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Multienzyme Complexes
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Oligopeptides
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Arecoline
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex