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(3) Design and Synthesis of Novel Nucleoside Analog Inhibitors Hepatitis C has infected about 2-3% of human population. Viral genome replication is crucial for viral life cycles and has been studied intensively. NS5B, the RNA-dependant RNA polymerase, which is at the center of viral replication, is one of major antiviral drug targets. Although there are extensive biochemical and steady-state kinetic studies on this polymerase, the elementary steps of nucleotide incorporation catalyzed by NS5B are still undefined. Using pre-steady state kinetic methods, we are studying the kinetic mechanism, processivity, fidelity, drug susceptibility, and drug resistance. The knowledge gained from these studies has severed as the basis for our rational design of nucleoside inhibitors. Currently, we are testing more than 140 nucleoside analogs which we have synthesized or obtained through collaboration in our cell-based assays. (1) Pre-Steady State Kinetic Studies of DNA Lesion Bypass Polymerases (2) Kinetic and Protein-Protein Interaction Studies of Human DNA Polymerases l, µ and TdT (3) Design and Synthesis of Novel Nucleoside Analog Inhibitors (4) Developing Anti-HCV Peptide-Based Inhibitors (5) Effects of HCV Protease NS3/4A on Human
Kinases Involved in Immune Response
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