Selective inhibition of hepatitis C virus infection by hydroxyzine and benztropine.
Hepatitis C virus (HCV) infection is a major biomedical problem worldwide as it causes severe liver disease in millions of humans around the world. Despite the recent approval of specific drugs targeting HCV replication to be used in combination with alpha interferon (IFN-α) and ribavirin, there is still an urgent need for pangenotypic, interferon-free therapies to fight this genetically diverse group of viruses. In this study, we used an unbiased screening cell culture assay to interrogate a chemical library of compounds approved for clinical use in humans. This system enables identifying nontoxic antiviral compounds targeting every aspect of the viral life cycle, be the target viral or cellular. The aim of this study was to identify drugs approved for other therapeutic applications in humans that could be effective components of combination therapies against HCV. As a result of this analysis, we identified 12 compounds with antiviral activity in cell culture, some of which had previously been identified as HCV inhibitors with antiviral activity in cell culture and had been shown to be effective in patients. We selected two novel HCV antivirals, hydroxyzine and benztropine, to characterize them by determining their specificity and genotype spectrum as well as by defining the step of the replication cycle targeted by these compounds. We found that both compounds effectively inhibited viral entry at a postbinding step of genotypes 1, 2, 3, and 4 without affecting entry of other viruses.
Centro Nacional De Biotecnología-Consejo Superior de Investigaciones Científicas (CNB-CSIC), Madrid, Spain.
Lidia
L
Mingorance
Centro Nacional De Biotecnología-Consejo Superior de Investigaciones Científicas (CNB-CSIC), Madrid, Spain.
Martina
M
Friesland
Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, Barcelona, Spain.
Mairene
M
Coto-Llerena
Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, Barcelona, Spain.
Sofía
S
Pérez-del-Pulgar
Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain.
Loreto
L
Boix
Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain.
Juan Manuel
JM
López-Oliva
Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain.
Jordi
J
Bruix
Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, Barcelona, Spain.
Xavier
X
Forns
Centro Nacional De Biotecnología-Consejo Superior de Investigaciones Científicas (CNB-CSIC), Madrid, Spain pgastaminza@cnb.csic.es.
Pablo
P
Gastaminza
D000998:Antiviral Agents / Q000627:therapeutic use*; D001590:Benztropine / Q000627:therapeutic use*; D001681:Biological Assay; D018929:Cell Culture Techniques; D004359:Drug Therapy, Combination; D005828:Genetics, Population; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D006919:Hydroxyzine / Q000627:therapeutic use*; D016898:Interferon-alpha / Q000627:therapeutic use*; D008099:Liver; D012254:Ribavirin / Q000627:therapeutic use*; D054852:Small Molecule Libraries; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D016898:Interferon-alpha; D054852:Small Molecule Libraries; D001590:Benztropine; D006919:Hydroxyzine; D012254:Ribavirin