title: Exploring dual electrophiles in peptide-based proteasome inhibitors: carbonyls and epoxides.
abstract: Peptide epoxyketones are potent and selective proteasome inhibitors. Selectivity is governed by the epoxyketone dual electrophilic warhead, which reacts with the N-terminal threonine 1,2-amino alcohol uniquely present in proteasome active sites. We studied a series of C-terminally modified oligopeptides featuring adjacent electrophiles based on the epoxyketone warhead. We found that the carbonyl moiety in the natural warhead is essential, but that the adjacent epoxide can be replaced by a carbonyl, though with considerable loss of activity.
authors: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2300 RA Leiden, The Netherlands. h.s.overkleeft@chem.leidenuniv.nl.
authors: Bo-Tao
authors: BT
authors: Xin
authors: Gerjan
authors: G
authors: de Bruin
authors: Martijn
authors: M
authors: Verdoes
authors: Dmitri V
authors: DV
authors: Filippov
authors: Gijs A
authors: GA
authors: van der Marel
authors: Herman S
authors: HS
authors: Overkleeft
mesh_terms: D004583:Electrons; D004852:Epoxy Compounds / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D009842:Oligopeptides / Q000737:chemistry; D010455:Peptides / Q000737:chemistry*; D061988:Proteasome Inhibitors / Q000737:chemistry*; D050050:Protein Carbonylation
chemical_list: D004852:Epoxy Compounds; D009842:Oligopeptides; D010455:Peptides; D061988:Proteasome Inhibitors; C078846:epoxomicin