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Chronic infection with hepatitis C virus (HCV) has emerged as a major health problem as it can lead to un-curable cirrhosis and liver cancer An estimated 170 million people worldwide have been infected with HCV. HCV is the leading cause of liver transplantation and results in up to 10,000 deaths annually in the U.S. Current treatments (interferon alone or with ribavirin) have met with limited success and often with undesired side effects.
Despite intense efforts dedicated to it in the past decade, many aspects of the disease as well as the biological life of the virus remains unclear. This has made the drug discovery extremely challenging. Antiviral agents that directly block essential viral enzymes have demonstrated a straightforward approach to developing new therapies for Hepatitis C. The viral RNA genome encodes a polyprotein including two proteases essential for virus replication: the NS2-3 protease and the NS3-4A protease.
In this project, we aim to identify and develop potent small molecule inhibitors targeting at Hepatitis C Virus NS2-3 Protease, for which there are no reported inhibitors, as potential therapeutic agents. The design of these molecules is based on the newly resolved crystal structure of the catalytic domain of the HCV NS2-3 protease. The concepts of "multivalent" and "multifunction" are incorporated into the design as new strategies to improve the efficiency of the inhibitors. It is expected that the small molecule inhibitors with similar symmetry to that of the NS2-3 protease dimer will demonstrate high selectivity and affinity for HCV NS2-3 protease. |
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