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Development of an Aryloxazole Class of Hepatitis C Virus Inhibitors Targeting the Entry Stage of the Viral Replication Cycle
He, Shanshan Li, Kelin Lin, Billy Hu, Zongyi Xiao, Jingbo Hu, Xin wang, Amy Q. Xu, Xin Ferrer, Mark Southall, Noel
He, Shanshan
Li, Kelin
Lin, Billy
Hu, Zongyi
Xiao, Jingbo
Hu, Xin
wang, Amy Q.
Xu, Xin
Ferrer, Mark
Southall, Noel
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Abstract
Reliance on hepatitis C virus (HCV) replicon systems and protein-based screening assays has led to treatments that target HCV viral replication proteins. The model does not encompass other viral replication cycle steps such as entry, processing, assembly and secretion, or viral host factors. We previously applied a phenotypic high-throughput screening platform based on an infectious HCV system and discovered an aryloxazole-based anti-HCV hit. Structure– activity relationship studies revealed several compounds exhibiting EC50 values below 100 nM. Lead compounds showed inhibition of the HCV pseudoparticle entry, suggesting a different mode of action from existing HCV drugs. Hit 7a and lead 7ii both showed synergistic effects in combination with existing HCV drugs. In vivo pharmacokinetics studies of 7ii showed high liver distribution and long half-life without obvious hepatotoxicity. The lead compounds are promising as preclinical candidates for the treatment of HCV infection and as molecular probes to study HCV pathogenesis.
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2017-06-21
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American Chemical Society
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Shanshan He, Kelin Li, Billy Lin, Zongyi Hu, Jingbo Xiao, Xin Hu, Amy Q. Wang, Xin Xu, Marc Ferrer, Noel Southall, Wei Zheng, Jeffrey Aubé, Frank J. Schoenen, Juan J. Marugan, T. Jake Liang, Kevin J. Frankowski
J Med Chem. 2017 Jul 27; 60(14): 6364–6383. Published online 2017 Jul 13. doi: 10.1021/acs.jmedchem.7b00561