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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

Chemical structures of HZ-1157 and LZ-110618-6.
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fig7: Chemical structures of HZ-1157 and LZ-110618-6.

Mentions: Afterwards, those anti-HCV active compounds selected from the HCV replicon assay were tested in the HCV NS3/4A-Seap reporter cell line. The results are shown in Table 3 and Figure 7. Of these compounds, HZ-1157 and LZ-110618-6 showed inhibitory effects on the HCV NS3/4A protease with IC50 values of 1.0 μmol/L and 0.68 μmol/L, respectively. Comparing their IC50 values in the HCV NS3/4A protease assay and HCV replicon assay, the IC50 value of HZ-1157 (1.0 μmol/L) in the HCV NS3/4A protease assay was close to its IC50 value in the HCV replicon assay (0.73 μmol/L). This result indicated that HZ-1157 inhibited HCV replication by targeting the viral NS3/4A protease. However, the IC50 value of LZ-110618-6 in the HCV NS3/4A protease assay (0.68 μmol/L) was much higher than its IC50 value in the HCV replicon assay (0.06 μmol/L). This suggests that LZ-110618-6 most likely has multiple targets in the HCV life cycle, and its anti-HCV activity could be partially due to the inhibition of the HCV NS3/4A protease.


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)

Chemical structures of HZ-1157 and LZ-110618-6.
© Copyright Policy
Related In: Results  -  Collection

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

fig7: Chemical structures of HZ-1157 and LZ-110618-6.
Mentions: Afterwards, those anti-HCV active compounds selected from the HCV replicon assay were tested in the HCV NS3/4A-Seap reporter cell line. The results are shown in Table 3 and Figure 7. Of these compounds, HZ-1157 and LZ-110618-6 showed inhibitory effects on the HCV NS3/4A protease with IC50 values of 1.0 μmol/L and 0.68 μmol/L, respectively. Comparing their IC50 values in the HCV NS3/4A protease assay and HCV replicon assay, the IC50 value of HZ-1157 (1.0 μmol/L) in the HCV NS3/4A protease assay was close to its IC50 value in the HCV replicon assay (0.73 μmol/L). This result indicated that HZ-1157 inhibited HCV replication by targeting the viral NS3/4A protease. However, the IC50 value of LZ-110618-6 in the HCV NS3/4A protease assay (0.68 μmol/L) was much higher than its IC50 value in the HCV replicon assay (0.06 μmol/L). This suggests that LZ-110618-6 most likely has multiple targets in the HCV life cycle, and its anti-HCV activity could be partially due to the inhibition of the HCV NS3/4A protease.

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