Vinyl ester-based cyclic peptide proteasome inhibitors |
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Authors: | Baldisserotto Anna Marastoni Mauro Fiorini Stella Pretto Loretta Ferretti Valeria Gavioli Riccardo Tomatis Roberto |
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Institution: | Department of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, Via Fossato di Mortara 17-19, I-44100 Ferrara, Italy. |
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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. |
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