title: Novel hepatitis C virus protease inhibitors: thiazolidine derivatives.
abstract: This study evaluated the inhibitory effects of thiazolidine derivatives on hepatitis C virus (HCV) protease and other human serine proteases. The inhibition efficacy was tested with a reversed-phase high-performance liquid chromatography (HPLC) assay system using a NS3-NS4A fusion protein as the HCV protease and a synthetic peptide substrate that mimics the NS5A-5B junction. Nine thiazolidine derivatives showed more than 50% inhibition at 50 microg/ml. The most potent derivative was RD4-6250, with 50% inhibition at a concentration of 2.3 microg/ml; this concentration was lower than those of other protease inhibitors reported previously. The most selective derivative was RD4-6205, with 50% inhibition at a concentration of 6.4 microg/ml, a lower concentration than those on other serine proteases (chymotrypsin, trypsin, plasmin, and elastase). These results suggest that the RD4-6205 skeleton is an important structure for inhibitory activity on the HCV protease NS3-NS4A.
authors.affiliation: Rational Drug Design Laboratories, 4-1-1, Misato, Fukushima, Matsukawa-Machi, 960-12, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sudo
authors.forename: Y
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: M
authors.initials: M
authors.lastname: Matsushima
authors.forename: M
authors.initials: M
authors.lastname: Fujiwara
authors.forename: K
authors.initials: K
authors.lastname: Konno
authors.forename: K
authors.initials: K
authors.lastname: Shimotohno
authors.forename: S
authors.initials: S
authors.lastname: Shigeta
authors.forename: T
authors.initials: T
authors.lastname: Yokota
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D020365:RNA Helicases; D012697:Serine Endopeptidases; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D004791:Enzyme Inhibitors; D020365:RNA Helicases; D012697:Serine Endopeptidases; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C108357:RD4 6250