Repurposing of the antihistamine chlorcyclizine and related compounds for treatment of hepatitis C virus infection

Sci Transl Med 8 April 2015:
Vol. 7, Issue 282, p. 282ra49
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3010286

Research Article

DRUG DISCOVERY

Shanshan He¹, Billy Lin¹, Virginia Chu¹, Zongyi Hu¹, Xin Hu², Jingbo Xiao², Amy Q. Wang², Cameron J. Schweitzer¹, Qisheng Li¹, Michio Imamura³, Nobuhiko Hiraga³, Noel Southall², Marc Ferrer², Wei Zheng², Kazuaki Chayama³, Juan J. Marugan² and T. Jake Liang¹,*

+ Author Affiliations

1. ¹Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
2. ²National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
3. ³Department of Medicine and Molecular Sciences, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 730-0053, Japan.

1. *Corresponding author. E-mail: jliang@nih.gov

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.

• Copyright © 2015, American Association for the Advancement of Science

Citation: S. He, B. Lin, V. Chu, Z. Hu, X. Hu, J. Xiao, A. Q. Wang, C. J. Schweitzer, Q. Li, M. Imamura, N. Hiraga, N. Southall, M. Ferrer, W. Zheng, K. Chayama, J. J. Marugan, T. J. Liang, Repurposing of the antihistamine chlorcyclizine and related compounds for treatment of hepatitis C virus infection. Sci. Transl. Med. 7, 282ra49 (2015).

Source