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

Over-the-counter allergy drug chlorcyclizine was identified and characterized as an anti-HCV drug in vitro and in vivo. Over-the-counter allergy drug inhibits viral infection A drug commonly used for a runny nose may now be repurposed for treating hepatitis C virus (HCV) infection—a virus that often goes undetected, but can exacerbate many liver diseases, including cirrhosis and cancer. The class of compounds, called antihistamines, which are used to relieve allergies, was uncovered by He et al. in a screen of a library of approved drugs, the NIH Chemical Genomics Center Pharmaceutical Collection. Among these, the first-generation antihistamine chlorcyclizine demonstrated high antiviral activity in cell culture and in mice with “humanized” livers, without evidence of drug resistance—a common problem with existing antivirals. Chlorcyclizine was specific for HCV, demonstrating no activity against 13 other viruses, including hepatitis B, and showed synergy with different classes of anti-HCV drugs, such as ribavirin, sofosbuvir, cyclosporin A, and interferon-α. Antihistamines are widely available, safe, and inexpensive, making them ideal for imminent translation to HCV-endemic countries in Asia and Africa. 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.