N-Terminal-prolonged vinyl ester-based peptides as selective proteasome beta 1 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 selecti...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2009-08, Vol.17 (15), p.5535-5540
Main Authors: Baldisserotto, Anna, Destro, Federica, Vertuani, Gianni, Marastoni, Mauro, Gavioli, Riccardo, Tomatis, Roberto
Format: Article
Language:English
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Summary: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 beta 1 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2009.06.025