Arecoline Tripeptide Inhibitors of Proteasome

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 1719 are the best compounds of the series, showing chymotryptic-like (β5) inhibition (IC50 ≅ 1 μM) and favorable pharmacokinetic properties.