Biochemical mechanism of hepatitis C virus inhibition by the broad-spectrum antiviral arbidol.
Hepatitis C affects approximately 3% of the world population, yet its current treatment options are limited to interferon-ribavirin drug regimens which achieve a 50-70% cure rate depending on the hepatitis C virus (HCV) genotype. Besides extensive screening for HCV-specific compounds, some well-established medicinal drugs have recently demonstrated an anti-HCV effect in HCV replicon cells. One of these drugs is arbidol (ARB), a Russian-made broad-spectrum antiviral agent, which we have previously shown to inhibit acute and chronic HCV infection. Here we show that ARB inhibits the cell entry of HCV pseudoparticles of genotypes 1a, 1b, and 2a in a dose-dependent fashion. ARB also displayed a dose-dependent inhibition of HCV membrane fusion, as assayed by using HCV pseudoparticles (HCVpp) and fluorescent liposomes. ARB inhibition of HCVpp fusion was found to be more effective on genotype 1a than on genotypes 1b and 2a. In vitro biochemical studies revealed association of ARB with membranelike environments such as detergents and with lipid membranes. This association was particularly prominent at acidic pH which is optimal for HCV-mediated fusion. Our results suggest that the affinity of ARB for lipid membranes could account for its anti-HCV actions, together with a differential level of interaction with key motifs in HCV glycoproteins of different genotypes.
Pécheur
Eve-Isabelle
EI
IFR128 Biosciences Lyon Gerland, Institut de Biologie et Chimie des Protéines, UMR 5086 CNRS-Université Claude Bernard Lyon I, 7 passage du Vercors, 69367 Lyon Cedex 07, France. e.pecheur@ ibcp.fr
Lavillette
Dimitri
D
Alcaras
Fanny
F
Molle
Jennifer
J
Boriskin
Yury S
YS
Roberts
Michael
M
Cosset
François-Loïc
FL
Polyak
Stephen J
SJ
D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003902:Detergents; D016174:Hepacivirus / Q000737:chemistry / Q000187:drug effects* / Q000472:pathogenicity; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008081:Liposomes; D008561:Membrane Fusion / Q000187:drug effects; D008563:Membrane Lipids / Q000037:antagonists & inhibitors / Q000737:chemistry; D008823:Micelles; D014771:Virion / Q000737:chemistry / Q000187:drug effects / Q000472:pathogenicity; D013440:Sulfides
D000998:Antiviral Agents; D003902:Detergents; D007211:Indoles; D008081:Liposomes; D008563:Membrane Lipids; D008823:Micelles; C086979:umifenovir; D013440:Sulfides