Novel hepatitis C virus protease inhibitors: thiazolidine derivatives |
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Authors: | K Sudo Y Matsumoto M Matsushima M Fujiwara K Konno K Shimotohno S Shigeta T Yokota |
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Affiliation: | Rational Drug Design Laboratories, 4-1-1, Misato, Fukushima, Matsukawa-Machi, 960-12, Japan. |
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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. |
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