Structure-based design of derivatives of tyropeptin A as the potent and selective inhibitors of mammalian 20S proteasome.
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.
Momose
Isao
I
Numazu Bio-Medical Research Institute, Microbial Chemistry Research Center, 18-24 Miyamoto, Numazu City, Shizuoka 410-0301, Japan. imomose@bikaken.or.jp
Umezawa
Yoji
Y
Hirosawa
Sehei
S
Iinuma
Hironobu
H
Ikeda
Daishiro
D
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
D004151:Dipeptides; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D061988:Proteasome Inhibitors; C449021:tyropeptin A; D010450:Endopeptidases; D002918:Chymotrypsin; C114177:peptidylglutamylpeptide hydrolase