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(5) Developing Anti-HCV Peptide-Based Inhibitors The non-structural proteins NS3, NS4A, NS4B, NS5A, and NS5B of HCV are processed from viral polyprotein precursor C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B by viral protease complex NS3/NS4A. NS3 has an N-terminal protease domain and a C-terminal helicase domain. The crystal structure of the NS3 protease domain shows that the N-terminus 28 residues are unfolded. In the complex with NS4A, the NS3 N-terminus folds into a beta sheet and an alpha helix, and the active site residues are slightly rearranged to form a catalytically favorable conformation. The NS3 protease is 995-fold more active in the presence than in the absence of NS4A. We are using the Stopped-Flow technology to study these conformational changes in NS3 after NS4A binding. We are also searching for tighter binding peptides to inhibit NS4A binding to NS3. The peptide inhibitors are then tested in the liver cell-line Huh 7-based HCV replicon assay. The inhibitory mechanism of the best peptide inhibitors will be studied further use confocal and multiphoton imaging and microscopy. (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 (4) Design and Synthesis of Novel Nucleoside Analog Inhibitors (5) Developing Anti-HCV Peptide-Based Inhibitors (6) Effects of HCV Protease NS3/4A on Human
Kinases Involved in Immune Response
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