Hepatitis C
Virus (HCV) infects 200 million individuals worldwide. Although several FDA approved drugs targeting the HCV
serine protease and
polymerase have shown promising results, there is a need for better drugs that are effective in treating a broader range of HCV genotypes and subtypes without being used in combination with
interferon and / or
ribavirin. Recently, the
crystal structure of the core of the HCV E2
protein (E2c) has been determined, providing structural information that can now be used to target the E2
protein and develop drugs that disrupt the early stages of HCV infection by blocking E2's interaction with different
host factors. By targeting sites containing conserved E2 amino acids in the CD81
binding site on HCV E2, one might also be able to develop drugs that block HCV infection in a
genotype-independent manner. Using the E2c structure as a template, a structural model of the E2
protein core (residues 421-645) was developed that includes the three
amino acid segments that are not present in the E2c
crystal structure. Blind docking of a diverse
library of 1715 small molecules to this model led to the identification of a set of 34 ligands predicted to bind near conserved
amino acid residues involved in the HCV E2:CD81 interaction.
Surface plasmon resonance was used to screen the ligand set for binding to recombinant E2 protein, and the best binders were subsequently tested to identify compounds that inhibit the infection of hepatocytes by HCV. One compound, 281816, blocked E2 binding to CD81 and inhibited
hepatocyte infection by HCV genotypes 1a, 1b, 2a, 2b, 4a and 6a with IC50's
ranging from 2.2 μM to 4.6 μM. Methods are described for preventing or treating HCV infection using
small molecule inhibitors such as 281816 that target E2 and disrupt its interactions.