Chronic hepatitis C is a major unsolved public health problem that afflicts 3.9 million people in the USA. Many patients eventually suffer from liver failure and/or hepatocellular carcinoma. Chronic hepatitis C is the most common reason for liver transplantation in the United States. Unfortunately, current treatments for chronic HCV remain relatively ineffective and frequently have side effects. The hypothesis of this proposal is: small molecules that selectively inhibit the HCV RNA dependent RNA polymerase (RDRP) will provide new effective treatments for chronic hepatitis C. A major problem in HCV research is the development of model systems to study HCV replication and identify effective molecular based therapeutics. The investigator has expressed an active HCV RNA dependent RNA polymerase in E. coli and can produce large quantities of polymerase for a variety of studies. This opens the door to identify molecules that inhibit HCV RDRP and to eventually test their ability to down-regulate HCV replication in vitro. The specific aims of this proposal are: 1) further purify and characterize recombinant HCV RNA- dependent RNA polymerase (RDRP), 2) develop a highly efficient HCV RDRP in vitro assay and test small molecules for their ability to directly inhibit HCV genome replication, and 3) initiate crystal growth feasibility studies with the long term goal of conducting structure-based design of new therapeutics for chronic hepatitis C.
