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.

Clinically Approved Ion Channel Inhibitors Close Gates for Hepatitis C Virus and Open Doors for Drug Repurposing in Infectious Viral Diseases

“…called the NCGC Pharmaceutical Collection (NPC) (6), and a small group of clinically approved ion channel inhibitors used to treat cardiac or neurologic conditions (7). These independent studies identified several structurally related compounds as potent HCV cell entry inhibitors both in vitro and in vivo.…”

“…Moreover, primary human hepatocytes do not express H 1 histamine receptor mRNA (40), although the antiviral activity of chlorcyclizine in these cells was readily detectable (6). Finally, histamine itself does not affect HCV infection, and two related compounds with divergent antihistamine activities have similar anti-HCV activities (6). Along the same lines, dopamine receptors and T-type Ca 2ϩ ion channels (CACNA1G, CACNA1H, CACNA1I) are not (or are poorly) expressed in Huh-7.5 cells (Ͻ0.18 reads per kilobase per million [RPKM]) (data not shown; T. Pietschmann, unpublished observation), in primary hepatocyte transcriptional profiles, and in human livers (the Human Protein Atlas [http://www.proteinatlas.org]).…”

“…They influence the function of muscarinic, ␣-adrenergic, and serotonergic receptors and can modulate cardiac channels, resulting in a relatively broad spectrum of side effects, including sedation, hyperactivity, insomnia, and convulsions (24). Among antihistamines with anti-HCV activity are both first-generation (chlorcyclizine, cyclizine, hydroxyzine, cyproheptadine, ketotifen, mequitazine, and trimeprazine) and second-generation (loratadine and desloratadine) antihistamines (4,6,24), which indicates that both drug classes include molecules that can target HCV.…”

“…In turn, this implies that HCV and the other above-mentioned viruses rely on these host factors for virus infection. However, based on transcriptional profiling, H 1 histamine receptors are not expressed in Huh-7.5 cells (39; T. Pietschmann, unpublished observation), a cell line routinely used in HCV research and the parent of the cell line used by He et al to identify numerous antihistamines as HCV inhibitors (6). Moreover, primary human hepatocytes do not express H 1 histamine receptor mRNA (40), although the antiviral activity of chlorcyclizine in these cells was readily detectable (6).…”

“…However, based on transcriptional profiling, H 1 histamine receptors are not expressed in Huh-7.5 cells (39; T. Pietschmann, unpublished observation), a cell line routinely used in HCV research and the parent of the cell line used by He et al to identify numerous antihistamines as HCV inhibitors (6). Moreover, primary human hepatocytes do not express H 1 histamine receptor mRNA (40), although the antiviral activity of chlorcyclizine in these cells was readily detectable (6). Finally, histamine itself does not affect HCV infection, and two related compounds with divergent antihistamine activities have similar anti-HCV activities (6).…”