Abstract: The inventors have discovered that an ATPase-deficient dominant-negative mutant NS3 protein of hepatitis C virus inhibits activity of the wild-type NS3 protein and inhibits replication of hepatitis C virus (HCV). The solved crystal structure of a multi-enzyme NS3 complex on a DNA substrate is also provided. The inventors have tested a peptide matching the sequence of a portion of NS3 that interacts with another NS3 molecule for inhibiting HCV replication. The peptide inhibits HCV replication. Accordingly, the invention provides a method of inhibiting HCV replication in cells infected with HCV involving transforming the cells with a vector expressing a dominant-negative mutant NS3 gene. The invention also provides a method of inhibiting HCV replication in cells infected with HCV involving administering to the cells a dominant-negative mutant NS3 protein. The invention also provides peptides and agents that inhibit HCV replication and methods of identifying agents that inhibit HCV replication.