The antimalarial ferroquine is an inhibitor of hepatitis C virus.
Hepatitis C virus (HCV) is a major cause of chronic liver disease. Despite recent success in improving anti-HCV therapy, additional progress is still needed to develop cheaper and interferon (IFN)-free treatments. Here, we report that ferroquine (FQ), an antimalarial ferrocenic analog of chloroquine, is a novel inhibitor of HCV. FQ potently inhibited HCV infection of hepatoma cell lines by affecting an early step of the viral life cycle. The antiviral activity of FQ on HCV entry was confirmed with pseudoparticles expressing HCV envelope glycoproteins E1 and E2 from six different genotypes. In addition to its effect on HCV entry, FQ also inhibited HCV RNA replication, albeit at a higher concentration. We also showed that FQ has no effect on viral assembly and virion secretion. Using a binding assay at 4°C, we showed that FQ does not prevent attachment of the virus to the cell surface. Furthermore, virus internalization was not affected by FQ, whereas the fusion process was impaired in the presence of FQ as shown in a cell-cell fusion assay. Finally, virus with resistance to FQ was selected by sequential passage in the presence of the drug, and resistance was shown to be conferred by a single mutation in E1 glycoprotein (S327A). By inhibiting cell-free virus transmission using a neutralizing antibody, we also showed that FQ inhibits HCV cell-to-cell spread between neighboring cells. Combinations of FQ with IFN, or an inhibitor of HCV NS3/4A protease, also resulted in additive to synergistic activity.


CONCLUSIONS
FQ is a novel, interesting anti-HCV molecule that could be used in combination with other direct-acting antivirals.
Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France.
Thibaut
T
Vausselin
Noémie
N
Calland
Sandrine
S
Belouzard
Véronique
V
Descamps
Florian
F
Douam
François
F
Helle
Catherine
C
François
Dimitri
D
Lavillette
Gilles
G
Duverlie
Ahmed
A
Wahid
Lucie
L
Fénéant
Laurence
L
Cocquerel
Yann
Y
Guérardel
Czeslaw
C
Wychowski
Christophe
C
Biot
Jean
J
Dubuisson
D000634:Aminoquinolines / Q000494:pharmacology*; D000998:Antiviral Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005296:Ferrous Compounds / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006526:Hepatitis C / Q000517:prevention & control; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage; D000075163:Metallocenes; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives; D014759:Viral Envelope Proteins / Q000187:drug effects / Q000235:genetics; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D053586:Virus Internalization / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000634:Aminoquinolines; D000998:Antiviral Agents; D005296:Ferrous Compounds; D016898:Interferon-alpha; D000075163:Metallocenes; D011392:Proline; D014759:Viral Envelope Proteins; D017361:Viral Nonstructural Proteins; C087035:E1 protein, Hepatitis C virus; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; C479230:ferroquine