N-terminal-prolonged vinyl ester-based peptides as selective proteasome beta1 subunit inhibitors.
The synthesis and biological properties of vinyl ester peptide-based molecules bearing linear N-terminal amino acids are reported. Compounds were tested in vitro for their capacity to inhibit the chymotryptic-, tryptic-like, and post-acidic activities of the proteasome. Some analogues showed selective inhibition of post-acidic (PGPH) activity, which is attributed to the beta1 subunit. Interestingly, active compounds demonstrated higher inhibitory activity toward 'standard' proteasomes than toward immunoproteasomes. The inhibitory potency was found to be related to the amino acidic sequence and to the length of the N-terminal residues. The new inhibitors demonstrated resistance to plasmatic proteases and a good capacity to permeate the cell membrane.
Baldisserotto
Anna
A
Department of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, Via Fossato di Mortara 17-19, I-44100 Ferrara, Italy.
Destro
Federica
F
Vertuani
Gianni
G
Marastoni
Mauro
M
Gavioli
Riccardo
R
Tomatis
Roberto
R
D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D013329:Structure-Activity Relationship
D010455:Peptides; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex