title: Structure-based design of derivatives of tyropeptin A as the potent and selective inhibitors of mammalian 20S proteasome.
abstract: Tyropeptin A, a new potent proteasome inhibitor, was produced by Kitasatospora sp. MK993-dF2. To enhance the inhibitory potency of tyropeptin A, we constructed the structural model of tyropeptin A bound to the site responsible for the chymotrypsin-like activity of mammalian 20S proteasome. Based on these modeling experiments, we designed and synthesized several derivatives of tyropeptin A. Among them, the most potent compound, TP-104, exhibited a 20-fold enhancement in its inhibitory potency compared to tyropeptin A. Additionally, TP-110 specifically inhibited the chymotrypsin-like activity, but did not inhibit the PGPH and the trypsin-like activities.
authors.affiliation: Numazu Bio-Medical Research Institute, Microbial Chemistry Research Center, 18-24 Miyamoto, Numazu City, Shizuoka 410-0301, Japan. imomose@bikaken.or.jp
authors.forename: Isao
authors.initials: I
authors.lastname: Momose
authors.forename: Yoji
authors.initials: Y
authors.lastname: Umezawa
authors.forename: Sehei
authors.initials: S
authors.lastname: Hirosawa
authors.forename: Hironobu
authors.initials: H
authors.lastname: Iinuma
authors.forename: Daishiro
authors.initials: D
authors.lastname: Ikeda
mesh_terms: D001665:Binding Sites; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D010450:Endopeptidases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D061988:Proteasome Inhibitors; D013329:Structure-Activity Relationship
chemical_list: D004151:Dipeptides; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D061988:Proteasome Inhibitors; C449021:tyropeptin A; D010450:Endopeptidases; D002918:Chymotrypsin; C114177:peptidylglutamylpeptide hydrolase