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  • A novel small-molecule inhibitor of hepatitis C virus replication acts by suppressing signal transducer and activator of transcription 3.

A novel small-molecule inhibitor of hepatitis C virus replication acts by suppressing signal transducer and activator of transcription 3.

The Journal of antimicrobial chemotherapy (2015-04-11)
Yuqiang Niu, Youhui Si, Yan Li, Xiaojing Chi, Xiang Li, Xiuying Liu, Duan Li, Min Cheng, Jingjing Fan, Shuyi Si, Wei Yang
ABSTRACT

Hepatitis C virus (HCV) infects hepatocytes and causes liver damage. The aim of this study was to identify new classes of host-targeting anti-HCV compounds that may provide novel approaches for antiviral treatment regimens. Cell culture-derived HCV (HCVcc), replicons and pseudoparticles were used in combination with high-throughput screening, reporter gene assays and cytotoxicity and signalling pathway analyses. A small-molecule inhibitor of HCV, N-(cyclopropyl(phenyl)methyl)thieno[2,3-d]pyrimidin-4-amine, designated IB-32, was identified by screening a compound library with a Jc1-luc HCVcc assay. By using various virus models, HCV replication was identified as the predominant step of IB-32's action. IB-32 inhibited HCVcc (genotype 2a) and HCV replicons (genotype 1b) at low nanomolar ranges (with IC50s of 40 ± 8 and 100 ± 15 nM, respectively). IB-32 was found to be non-toxic when tested against a panel of human cell lines in vitro at the effective antiviral dose. Mechanistically, IB-32 strongly inhibited STAT3 (Tyr705) phosphorylation, a necessary cellular factor for HCV replication and a pivotal therapeutic target for multiple cancers. Furthermore, the inhibition of HCV replication by IB-32 was augmented in cells with STAT3 knockdown. In contrast, the inhibitory effect of IB-32 was attenuated in cells overexpressing a constitutively active form of STAT3. The results presented here identify a promising STAT3-targeting anti-HCV therapeutic candidate. This novel small molecule could be further optimized and developed for use as both an antiviral and an anti-cancer drug.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
MISSION® esiRNA, targeting human SLC25A5
Sigma-Aldrich
MISSION® esiRNA, targeting mouse Stat3
Sigma-Aldrich
MISSION® esiRNA, targeting human STAT3
Sigma-Aldrich
S3I-201, ≥97% (HPLC)