title: Repurposing of the antihistamine chlorcyclizine and related compounds for treatment of hepatitis C virus infection.
abstract: 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.
authors: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Shanshan
authors: S
authors: He
authors: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Billy
authors: B
authors: Lin
authors: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Virginia
authors: V
authors: Chu
authors: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Zongyi
authors: Z
authors: Hu
authors: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors: Xin
authors: X
authors: Hu
authors: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors: Jingbo
authors: J
authors: Xiao
authors: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors: Amy Q
authors: AQ
authors: Wang
authors: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Cameron J
authors: CJ
authors: Schweitzer
authors: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Qisheng
authors: Q
authors: Li
authors: Department of Medicine and Molecular Sciences, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 730-0053, Japan.
authors: Michio
authors: M
authors: Imamura
authors: Department of Medicine and Molecular Sciences, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 730-0053, Japan.
authors: Nobuhiko
authors: N
authors: Hiraga
authors: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors: Noel
authors: N
authors: Southall
authors: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors: Marc
authors: M
authors: Ferrer
authors: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors: Wei
authors: W
authors: Zheng
authors: Department of Medicine and Molecular Sciences, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 730-0053, Japan.
authors: Kazuaki
authors: K
authors: Chayama
authors: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors: Juan J
authors: JJ
authors: Marugan
authors: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. jliang@nih.gov.
authors: T Jake
authors: TJ
authors: Liang
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000187:drug effects; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D057166:High-Throughput Screening Assays; D006633:Histamine Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D016513:Mice, SCID; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D015203:Reproducibility of Results; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D006633:Histamine Antagonists; D010879:Piperazines; C084597:chlorcyclizine