Arecoline Tripeptide Inhibitors of Proteasome

• Published in: Journal of medicinal chemistry 2004-03, Vol.47 (6), p.1587-1590
• Main Authors: Marastoni, Mauro, Baldisserotto, Anna, Canella, Alessandro, Gavioli, Riccardo, Risi, Carmela De, Pollini, Gian Piero, Tomatis, Roberto
• Format: Article
• Language: English
• Subjects: Arecoline - analogs & derivatives; Arecoline - chemical synthesis; Arecoline - pharmacology; Biological and medical sciences; Cholinergic system; Cysteine Endopeptidases - blood; Cysteine Endopeptidases - chemistry; Cysteine Endopeptidases - metabolism; Cysteine Proteinase Inhibitors - chemical synthesis; Cysteine Proteinase Inhibitors - pharmacology; Drug Stability; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Humans; Medical sciences; Multienzyme Complexes - blood; Multienzyme Complexes - chemistry; Multienzyme Complexes - metabolism; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Oligopeptides - chemical synthesis; Oligopeptides - pharmacology; Pharmacology. Drug treatments; Proteasome Endopeptidase Complex
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0309102

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 (β5) inhibition (IC50 ≅ 1 μM) and favorable pharmacokinetic properties.