2. Academic Validation
  3. Development of an Aryloxazole Class of Hepatitis C Virus Inhibitors Targeting the Entry Stage of the Viral Replication Cycle

Development of an Aryloxazole Class of Hepatitis C Virus Inhibitors Targeting the Entry Stage of the Viral Replication Cycle

  • J Med Chem. 2017 Jul 27;60(14):6364-6383. doi: 10.1021/acs.jmedchem.7b00561.
Shanshan He 1,  Kelin Li 2,  Billy Lin 1,  Zongyi Hu 1,  Jingbo Xiao 3,  Xin Hu 3,  Amy Q Wang 3,  Xin Xu 3,  Marc Ferrer 3,  Noel Southall 3,  Wei Zheng 3,  Jeffrey Aubé 2,  Frank J Schoenen 2,  Juan J Marugan 3,  T Jake Liang 1,  Kevin J Frankowski 2
Affiliations

Affiliations

  • 1 Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , 10 Center Drive, Bethesda, Maryland 20892-1800, United States.
  • 2 University of Kansas Specialized Chemistry Center, University of Kansas , Lawrence, Kansas 66047, United States.
  • 3 Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
PMID: 28636348 DOI: 10.1021/acs.jmedchem.7b00561
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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