Discovering novel anti-HCV compounds with inhibitory activities toward HCV NS3/4A protease.
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Among them, two representative compounds HZ-1157 and LZ-110618-6 inhibited HCV NS3/4A protease with IC50 values of 1.0 and 0.68 μmol/L, respectively.Furthermore, HZ-1157 and LZ-110618-6 inhibited HCV infection in vitro with IC50 values of 0.82 and 0.11 μmol/L, respectively.Some 2,4-diaminoquinazoline derivatives and carboxamide analogues have been identified as novel anti-HCV compounds.
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PubMed Central - PubMed
Affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
ABSTRACT
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Aim: To discover novel hepatitis C virus (HCV) inhibitors and elucidate the mechanism of action of the active compounds. Methods: HCV subgenomic replicon-based luciferase reporter cell line was used to screen 1200 synthetic compounds with novel structures. Huh7.5.1 cell line stably transfected with HCV NS3/4A protease reporter was established to investigate the anti-HCV mechanism of the active compounds. The active compounds were further examined in an in vitro HCV infection assay to confirm their anti-HCV activity. Results: After two-round screening in the anti-HCV replicon assay, some 2,4-diaminoquinazoline derivatives and carboxamide analogues were found to possess anti-HCV replicon activities (the IC50 values were less than 5 μmol/L). Among them, two representative compounds HZ-1157 and LZ-110618-6 inhibited HCV NS3/4A protease with IC50 values of 1.0 and 0.68 μmol/L, respectively. Furthermore, HZ-1157 and LZ-110618-6 inhibited HCV infection in vitro with IC50 values of 0.82 and 0.11 μmol/L, respectively. Conclusion: Some 2,4-diaminoquinazoline derivatives and carboxamide analogues have been identified as novel anti-HCV compounds. Related in: MedlinePlus |
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fig1: The schematic diagram of HCV NS3/4A-Seap expression plasmids. The Seap gene with an N-terminal signal was fused in-frame to the HCV NS3/4A coding sequence. NS3/4A and Seap amino acids in the fusion regions are shown by capitalized characters. HDS is the catalytic triad of the HCV NS3 protease. The S to A mutation in the catalytic triad results in a disabled NS3 protease. The NS4A/4B cleavage site is indicated by an arrow. Mentions: For the pSelect-NS3/4A-Seap plasmid, the NS3/4A coding sequence, including the cleavage site, was amplified from the full length JFH1 strain plasmid pJFH1T (genotype 2a) by PCR with the forward primer 5′-ccatggTTGCTCCCATCACTGCTT-3′ and the reverse primer 5′-ccatggGCATTCCTCCATCTCATCAA-3′ and cloned into the NcoI site of the pSELECT-zeo-Seap vector (InvivoGen, San Diego, California, USA). The schematic diagram of this plasmid is shown in Figure 1. For the pSelect-NS3/4A(mut)–Seap plasmid, the serine of the HDS catalytic triad was changed to alanine (S139A). |
View Article: PubMed Central - PubMed
Affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Aim: To discover novel hepatitis C virus (HCV) inhibitors and elucidate the mechanism of action of the active compounds.
Methods: HCV subgenomic replicon-based luciferase reporter cell line was used to screen 1200 synthetic compounds with novel structures. Huh7.5.1 cell line stably transfected with HCV NS3/4A protease reporter was established to investigate the anti-HCV mechanism of the active compounds. The active compounds were further examined in an in vitro HCV infection assay to confirm their anti-HCV activity.
Results: After two-round screening in the anti-HCV replicon assay, some 2,4-diaminoquinazoline derivatives and carboxamide analogues were found to possess anti-HCV replicon activities (the IC50 values were less than 5 μmol/L). Among them, two representative compounds HZ-1157 and LZ-110618-6 inhibited HCV NS3/4A protease with IC50 values of 1.0 and 0.68 μmol/L, respectively. Furthermore, HZ-1157 and LZ-110618-6 inhibited HCV infection in vitro with IC50 values of 0.82 and 0.11 μmol/L, respectively.
Conclusion: Some 2,4-diaminoquinazoline derivatives and carboxamide analogues have been identified as novel anti-HCV compounds.