He Shanshan, Li Kelin, Lin Billy, Hu Zongyi, Xiao Jingbo, Hu Xin, Wang Amy Q, Xu Xin, Ferrer Marc, Southall Noel, Zheng Wei, Aubé Jeffrey, Schoenen Frank J, Marugan Juan J, Liang T Jake, Frankowski Kevin J
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.
University of Kansas Specialized Chemistry Center, University of Kansas , Lawrence, Kansas 66047, United States.
J Med Chem. 2017 Jul 27;60(14):6364-6383. doi: 10.1021/acs.jmedchem.7b00561. Epub 2017 Jul 13.
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 EC 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.
对丙型肝炎病毒（HCV）复制子系统和基于蛋白质的筛选试验的依赖导致了针对HCV病毒复制蛋白的治疗方法。该模型并未涵盖病毒复制周期的其他步骤，如进入、加工、组装和分泌，也未涉及病毒宿主因子。我们之前应用了基于感染性HCV系统的表型高通量筛选平台，并发现了一种基于芳基恶唑的抗HCV活性化合物。构效关系研究揭示了几种EC值低于100 nM的化合物。先导化合物显示出对HCV假病毒颗粒进入的抑制作用，表明其作用模式与现有HCV药物不同。活性化合物7a和先导化合物7ii与现有HCV药物联合使用时均显示出协同效应。7ii的体内药代动力学研究表明其在肝脏中的分布较高且半衰期较长，且无明显肝毒性。这些先导化合物有望成为治疗HCV感染的临床前候选药物以及研究HCV发病机制的分子探针。
