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Discovering novel anti-HCV compounds with inhibitory activities toward HCV NS3/4A protease.

Yu Y, Jing JF, Tong XK, He PL, Li YC, Hu YH, Tang W, Zuo JP - Acta Pharmacol. Sin. (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

ABSTRACT

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.

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Related in: MedlinePlus

The effects of LZ-110618-6 and HZ-1157 in an HCV infection assay. Compounds HZ-1157 and LZ-110618-6 were tested for their anti-HCV activities using an infectious HCV virus (J399EM) in Huh7.5.1 cells. Cells were first infected with J399EM virus, and then compounds were added and co-cultured for 72 h. The inhibition rate and cytotoxicity rate were calculated against control wells without compounds. The representative result is from two independent experiments with the same results.
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fig8: The effects of LZ-110618-6 and HZ-1157 in an HCV infection assay. Compounds HZ-1157 and LZ-110618-6 were tested for their anti-HCV activities using an infectious HCV virus (J399EM) in Huh7.5.1 cells. Cells were first infected with J399EM virus, and then compounds were added and co-cultured for 72 h. The inhibition rate and cytotoxicity rate were calculated against control wells without compounds. The representative result is from two independent experiments with the same results.

Mentions: HZ-1157 and LZ-110618-6 were further tested against an infectious HCV virus (J399EM) which can infect and replicate in Huh7.5.1 cells in vitro. The results are shown in Figure 8. HZ-1157 and LZ-110618-6 effectively inhibited J399EM virus replication in Huh7.5.1 cells with IC50 values of 0.82 μmol/L and 0.11 μmol/L, respectively. Comparing the results of HZ-1157 and LZ-110618-6 in three assay systems (HCV replicon, infectious HCV and HCV NS3/4A protease), HZ-1157 showed similar IC50 values across all tests (0.73 μmol/L vs 0.82 μmol/L vs 1.0 μmol/L), indicating that HZ-1157 is a specific inhibitor of the HCV NS3/4A protease. However, the IC50 values of LZ-110618-6 differed across the three assay systems (0.06 vs 0.11 vs 0.68 μmol/L), as LZ-110618-6 was more active in assay systems that involve virus replication. This may indicate that LZ-110618-6 inhibits viral components other than the NS3/4A protease (see the Discussion section below). The exact anti-HCV mechanism through which LZ-110618-6 acts remains to be further investigated.


Discovering novel anti-HCV compounds with inhibitory activities toward HCV NS3/4A protease.

Yu Y, Jing JF, Tong XK, He PL, Li YC, Hu YH, Tang W, Zuo JP - Acta Pharmacol. Sin. (2014)

The effects of LZ-110618-6 and HZ-1157 in an HCV infection assay. Compounds HZ-1157 and LZ-110618-6 were tested for their anti-HCV activities using an infectious HCV virus (J399EM) in Huh7.5.1 cells. Cells were first infected with J399EM virus, and then compounds were added and co-cultured for 72 h. The inhibition rate and cytotoxicity rate were calculated against control wells without compounds. The representative result is from two independent experiments with the same results.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4125721&req=5

fig8: The effects of LZ-110618-6 and HZ-1157 in an HCV infection assay. Compounds HZ-1157 and LZ-110618-6 were tested for their anti-HCV activities using an infectious HCV virus (J399EM) in Huh7.5.1 cells. Cells were first infected with J399EM virus, and then compounds were added and co-cultured for 72 h. The inhibition rate and cytotoxicity rate were calculated against control wells without compounds. The representative result is from two independent experiments with the same results.
Mentions: HZ-1157 and LZ-110618-6 were further tested against an infectious HCV virus (J399EM) which can infect and replicate in Huh7.5.1 cells in vitro. The results are shown in Figure 8. HZ-1157 and LZ-110618-6 effectively inhibited J399EM virus replication in Huh7.5.1 cells with IC50 values of 0.82 μmol/L and 0.11 μmol/L, respectively. Comparing the results of HZ-1157 and LZ-110618-6 in three assay systems (HCV replicon, infectious HCV and HCV NS3/4A protease), HZ-1157 showed similar IC50 values across all tests (0.73 μmol/L vs 0.82 μmol/L vs 1.0 μmol/L), indicating that HZ-1157 is a specific inhibitor of the HCV NS3/4A protease. However, the IC50 values of LZ-110618-6 differed across the three assay systems (0.06 vs 0.11 vs 0.68 μmol/L), as LZ-110618-6 was more active in assay systems that involve virus replication. This may indicate that LZ-110618-6 inhibits viral components other than the NS3/4A protease (see the Discussion section below). The exact anti-HCV mechanism through which LZ-110618-6 acts remains to be further investigated.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus