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 17-19 are the best compounds of the series, showing chymotryptic-like (beta5) inhibition (IC(50) congruent with 1 microM) and favorable pharmacokinetic properties.
Marastoni
Mauro
M
Department of Pharmaceutical Sciences and Biotechnology Center, and Department of Biochemistry and Molecular Biology, University of Ferrara, I-44100 Ferrara, Italy. mru@unife.it
Baldisserotto
Anna
A
Canella
Alessandro
A
Gavioli
Riccardo
R
Risi
Carmela De
CD
Pollini
Gian Piero
GP
Tomatis
Roberto
R
D001115:Arecoline / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D009097:Multienzyme Complexes / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex
D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D009842:Oligopeptides; D001115:Arecoline; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex