Grant: Operating Grant

Hepatitis C virus (HCV) infection is a serious health issue affecting more than 250,000 Canadians, with no cure currently available and limited treatment options. Thus, there is a strong interest in elucidating the role of human and viral proteins to better understand the cellular pathways essential for the life cycle of this virus and thereby develop novel diagnostic markers and new therapeutic drugs against HCV. While many proteins have functions that are well characterized and understood, little is known of the complex interactions of the entire cellular protein pool. Recently, we developed molecular tools, activity-based probes, aimed at understanding the protein functions of entire enzyme families. By applying these tools on human cells and HCV-infected mouse models, we have shown that the activity of the liver enzyme carboxylesterase 1 (CES1) is influenced by HCV and is necessary for efficient viral infection. In the current proposal, we intend to use activity-based probes to understand how the activity of CES1 correlates with HCV infectivity in human liver biopsies and if CES1 activity can be used as an activity-based marker of HCV infection. As HCV modifies the lipid metabolism of the liver, novel activity-based probes will also be used to analyze the effects of HCV on lipid enzymes such as fatty acid synthase (FAS). Using our mouse model for HCV infection, we will assess and visualize the effects of known CES1 and FAS inhibitory drugs on cellular lipids and HCV levels using modern microscopes. If proven successful, these inhibitors could be developed into new drugs against HCV infection.