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Peptide inhibitors of Hepatitis C virus core oligomerization and virus production

¹ The Scripps Research Institute-Florida;
² Institut de Biologie et Chimie des Proteines

³ E-mail: strosber{at}scripps.edu

Hepatitis C Virus (HCV) nucleocapsid assembly requires dimerization of the core protein, an essential step in the formation of the viral particle. We developed a novel quantitative assay for monitoring this protein-protein interaction, with the goal of identifying inhibitors of core dimerization that might block HCV production in infected Huh-7.5 hepatoma cells. Two core-derived, 18-residue peptides were found which inhibited respectively by 68% and 63%, the dimerization of a 1-to-106 fragment of core (core106). A third, related 15-residue peptide displayed 50% inhibition, with an IC50 of 21.9 µM. This peptide was shown, by fluorescence polarization, to bind directly to core106 with a Kd of 1.9 µM and was displaced by the unlabeled peptide with an IC50 of 18.7 µM. When measured by Surface Plasmon Resonance, the same peptide bound core169, with a Kd of 7.2 µM. When added to HCV-infected cells, each of the three peptides blocked release but not replication of infectious virus. When measured by Real Time RT-PCR the RNA levels were reduced by 7 fold. The 15-residue peptide had no effect on HIV propagation. Such inhibitors may thus constitute useful tools to investigate the role of core dimerization in the viral cycle.

Received 5 November 2008; accepted 4 February 2009.