He Shanshan, Lin Billy, Chu Virginia, Hu Zongyi, Hu Xin, Xiao Jingbo, Wang Amy Q, Schweitzer Cameron J, Li Qisheng, Imamura Michio, Hiraga Nobuhiko, Southall Noel, Ferrer Marc, Zheng Wei, Chayama Kazuaki, Marugan Juan J, Liang T Jake
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
Sci Transl Med. 2015 Apr 8;7(282):282ra49. doi: 10.1126/scitranslmed.3010286.
Hepatitis C virus (HCV) infection affects an estimated 185 million people worldwide, with chronic infection often leading to liver cirrhosis and hepatocellular carcinoma. Although HCV is curable, there is an unmet need for the development of effective and affordable treatment options. Through a cell-based high-throughput screen, we identified chlorcyclizine HCl (CCZ), an over-the-counter drug for allergy symptoms, as a potent inhibitor of HCV infection. CCZ inhibited HCV infection in human hepatoma cells and primary human hepatocytes. The mode of action of CCZ is mediated by inhibiting an early stage of HCV infection, probably targeting viral entry into host cells. The in vitro antiviral effect of CCZ was synergistic with other anti-HCV drugs, including ribavirin, interferon-α, telaprevir, boceprevir, sofosbuvir, daclatasvir, and cyclosporin A, without significant cytotoxicity, suggesting its potential in combination therapy of hepatitis C. In the mouse pharmacokinetic model, CCZ showed preferential liver distribution. In chimeric mice engrafted with primary human hepatocytes, CCZ significantly inhibited infection of HCV genotypes 1b and 2a, without evidence of emergence of drug resistance, during 4 and 6 weeks of treatment, respectively. With its established clinical safety profile as an allergy medication, affordability, and a simple chemical structure for optimization, CCZ represents a promising candidate for drug repurposing and further development as an effective and accessible agent for treatment of HCV infection.
丙型肝炎病毒（HCV）感染估计影响全球1.85亿人，慢性感染常导致肝硬化和肝细胞癌。尽管HCV感染可治愈，但对于开发有效且可负担得起的治疗方案仍存在未满足的需求。通过基于细胞的高通量筛选，我们确定了盐酸氯环利嗪（CCZ）——一种用于治疗过敏症状的非处方药——为HCV感染的有效抑制剂。CCZ可抑制人肝癌细胞和原代人肝细胞中的HCV感染。CCZ的作用方式是通过抑制HCV感染的早期阶段，可能是靶向病毒进入宿主细胞。CCZ的体外抗病毒作用与其他抗HCV药物（包括利巴韦林、干扰素-α、特拉匹韦、波普瑞韦、索磷布韦、达卡他韦和环孢素A）具有协同作用，且无明显细胞毒性，表明其在丙型肝炎联合治疗中的潜力。在小鼠药代动力学模型中，CCZ显示出肝脏优先分布。在植入原代人肝细胞的嵌合小鼠中，CCZ在治疗4周和6周期间分别显著抑制了HCV 1b型和2a型的感染，且没有出现耐药性的迹象。凭借其作为过敏药物已确立的临床安全性、可负担性以及易于优化的简单化学结构，CCZ是药物重新利用和进一步开发成为治疗HCV感染的有效且可及药物的有希望的候选者。
