title: A cell-permeable inhibitor and activity-based probe for the caspase-like activity of the proteasome.
abstract: The ubiquitin-proteasome pathway degrades the majority of proteins in mammalian cells and plays an essential role in the generation of antigenic peptides presented by major histocompatibility class I molecules. Proteasome inhibitors are of great interest as research tools and drug candidates. Most work on proteasome inhibitors has focused on the inhibition of the chymotryptic-like (beta5) sites; little attention has been paid to the inhibition of two other types of active sites, the trypsin-like (beta2) and the caspase-like (beta1). We report here the development of the first cell-permeable and highly selective inhibitors (4 and 5) of the proteasome's caspase-like site. The selectivity of the compounds is directly and unambiguously established by Staudinger-Bertozzi labeling of proteasome subunits covalently modified with azide-functionalized inhibitor 5. This labeling reveals that the caspase-like site of the immunoproteasome (beta1i) is a preferred target of this compound. These compounds can be used as tools to study roles of beta1 and beta1i sites in generation of specific antigenic peptides and their potential role as co-targets of anti-cancer drugs.
authors: Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, PO Box 9502, 2300 RA Leiden, Netherlands.
authors: Paul F
authors: PF
authors: van Swieten
authors: Emlyn
authors: E
authors: Samuel
authors: Rosa Orient
authors: RO
authors: Hernández
authors: Adrianus M C H
authors: AM
authors: van den Nieuwendijk
authors: Michiel A
authors: MA
authors: Leeuwenburgh
authors: Gijsbert A
authors: GA
authors: van der Marel
authors: Benedikt M
authors: BM
authors: Kessler
authors: Herman S
authors: HS
authors: Overkleeft
authors: Alexei F
authors: AF
authors: Kisselev
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001386:Azides / Q000737:chemistry; D001665:Binding Sites; D020169:Caspases / Q000737:chemistry / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects* / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D008956:Models, Chemical; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000276:immunology; D061988:Proteasome Inhibitors
chemical_list: D000970:Antineoplastic Agents; D001386:Azides; D015853:Cysteine Proteinase Inhibitors; D061988:Proteasome Inhibitors; D020169:Caspases; D046988:Proteasome Endopeptidase Complex