Original Article

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

Authors: Ye YU, Jing-feng JING, Xian-kun TONG, Pei-lan HE, Yuan-chao LI, You-hong HU, Wei TANG, Jian-ping ZUO
DOI: 10.1038/aps.2014.55


Ye YU#, Jing-feng JING#, Xian-kun TONG*, Pei-lan HE, Yuan-chao LI, You-hong HU, Wei TANG, Jian-ping ZUO*
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.

Keywords: hepatitis C virus; NS3/4A protease; secreted embryonic alkaline phosphatase (Seap); 2,4-diaminoquinazoline; carboxamide; telaprevir

This work was sponsored by the Ministry of Science and Technology of PRC (National Basic Research Program of China, 973 Program, 2013CB911104). The HCV infectious virus J399EM and the HCV replicon cell line J399LM were kindly provided by Professor Xin-wen CHEN, Wuhan Institute of Virology, Chinese Academy of Sciences.

# The first two authors contributed equally to this work.
* To whom correspondence should be addressed.
E-mail jpzuo@mail.shcnc.ac.cn (Jian-ping ZUO); xktong@mail.shcnc.ac.cn (Xian-kun TONG)
Received 2014-05-12 Accepted 2014-05-22

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