Polyphenols Inhibit Hepatitis C Virus Entry by a New Mechanism of Action.
J Virol. 2015 Jul 22. Epub 2015 Jul 22. PMID: 26202241
: Despite the validation of direct acting antivirals for hepatitis C treatment, discovery of new compounds with different modes of action may still be of importance for the treatment of special patient populations. We recently identified a natural molecule, epigallocatechin-3-gallate (EGCG) as an inhibitor of hepatitis C virus (HCV) targeting the viral particle. The aim of this work was to discover new natural compounds with higher anti-HCV activity than EGCG and determine their mode of action. Eight natural molecules with structure similarity to EGCG were selected. HCV JFH1 in cell culture and HCV pseudoparticle systems were used to determine antiviral activity and mechanism of action of the compounds. We identified delphinidin, a polyphenol belonging to the anthocyanidin family, as a new inhibitor of HCV entry. Delphinidin inhibits HCV entry, in a pan-genotypic manner, by acting directly on the viral particle and impairing its attachment to the cell surface. Importantly, it is also active against HCV in primary human hepatocytes with no apparent cytotoxicity and in combination with interferon and boceprevir in cell culture. Different approaches showed that neither aggregation nor destruction of the particle occurred. Cryo-transmission electron microscopy observations of HCV pseudoparticles treated with delphinidin or EGCG showed a bulge on particles that was not observed in control conditions. In conclusion, EGCG and delphinidin inhibit HCV entry by a new mechanism, i.e. alteration of the viral particle structure that impairs its attachment to the cell surface.
IMPORTANCE: In this article, we identify a new inhibitor of hepatitis C virus (HCV) infection, delphinidin, which prevents HCV entry. This natural compound, a plant pigment responsible for the blue-purple color of flowers and berries, belongs to the flavonoid family, like the catechin EGCG, the major component present in green tea extract, which is also an inhibitor of HCV entry. We studied the mode of action of these two compounds against HCV and demonstrated that they both act directly on the virus, inducing a bulging of the viral envelope. This deformation might be responsible for the inhibition of the virus attachment to the cell surface. The discovery of such anti-HCV inhibitors with an unusual mode of action is important to better characterize the mechanism of HCV entry into hepatocyte and to help developing a new class of anti-HCV entry inhibitors.