Structure-based design of hepatitis C virus inhibitors.
The limitations of current treatment for chronic hepatitis C virus (HCV) infection have prompted the development of novel therapeutic strategies targeting events specific to viral replication. Over the past decade, advances in the study of HCV molecular biology have led to the identification of cis-acting RNA sequences and viral enzymatic activities which present attractive targets for inhibition. High-resolution, three-dimensional structures of the HCV serine protease, helicase and RNA-dependent RNA polymerase have been determined through X-ray crystallographic studies. More recently, solution structures of these proteins and the HCV internal ribosome entry site have been evaluated by nuclear magnetic resonance spectroscopy and electron microscopy. Mutational analysis and structural characterization of these macromolecules in complex with bound substrates, cofactors and inhibitors has further defined the various electrochemical interactions which mediate protein-protein, protein-RNA and other intermolecular contacts. This review will discuss the available structural data with respect to the rational design of HCV enzyme inhibitors and the development of antisense-based therapeutic strategies, such as RNA interference.