title: Vinyl ester-based cyclic peptide proteasome inhibitors.
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.
authors.affiliation: Department of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, Via Fossato di Mortara 17-19, I-44100 Ferrara, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Baldisserotto
authors.forename: Mauro
authors.initials: M
authors.lastname: Marastoni
authors.forename: Stella
authors.initials: S
authors.lastname: Fiorini
authors.forename: Loretta
authors.initials: L
authors.lastname: Pretto
authors.forename: Valeria
authors.initials: V
authors.lastname: Ferretti
authors.forename: Riccardo
authors.initials: R
authors.lastname: Gavioli
authors.forename: Roberto
authors.initials: R
authors.lastname: Tomatis
mesh_terms: D002851:Chromatography, High Pressure Liquid; D002918:Chymotrypsin / Q000378:metabolism; D003500:Cyclization; D010450:Endopeptidases / Q000378:metabolism; D004952:Esters / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D011487:Protein Conformation; D021241:Spectrometry, Mass, Electrospray Ionization; D014357:Trypsin / Q000378:metabolism; D014753:Vinyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004952:Esters; D010456:Peptides, Cyclic; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D014753:Vinyl Compounds; D010450:Endopeptidases; D002918:Chymotrypsin; D014357:Trypsin; C114177:peptidylglutamylpeptide hydrolase