Antivirals for Hepatitis C Targeting Phosphoinositide Metabolism

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DESCRIPTION (provided by applicant): Dr. Gelman, an MD/PhD with prior training in organic chemistry and infectious diseases, whose immediate career goal is advanced training in molecular virology and related disciplines and whose long-term career goal is a position in academic medicine, proposes to study the hepatitis C virus using a novel class of small molecules, the PI4K inhibitors. The proposed work will take place at Stanford University, in Dr. Jeffrey Glenn's laboratory, with co-mentor Dr. Kevan Shokat (UCSF Cellular and Molecular Pharmacology) and consultants Dr. Gary Peltz (Anesthesia; expertise in pharmacokinetics and drug metabolism) and Dr. Michael Lin (Pediatrics/Bioengineering; expertise in imaging biological molecules in living cells). Stanford has a vibrant Infectious Diseases division and extensive career support for postdoctoral fellows as they prepare to make the transition to faculty positions. The hepatitis C virus (HCV) infects between 2-3% of the global population, or roughly 170 million people. Chronic HCV infection carries a 25% risk of cirrhosis and a smaller but significant risk of life-threatening hepatocellular cancer. Cirrhosis due to HCV is the leading indication for liver transplant in the US, but HCV invariably recurs in the transplanted organ. The current standard of care for HCV treatment is a 12-48 week (depending on genotype and response) course of peginterferon-ribavirin, which is costly, has multiple serious side effects, and is only 50-80% effective. Although multiple new classes of anti-HCV therapies are in various stages of development, multidrug combination therapy is likely to be necessary for effective control of the infection. The HCV nonstructural protein NS5A interacts specifically with membrane phosphoinositide PI(4,5)P2, or PIP2. Both this interaction and the phosphoinositide 4-kinase (PI4K) activity that generates PIP2 appear to be necessary for viral replication. The proposed research involves characterization of the potential of compounds designed to inhibit PI4K as (1) a novel class of antivirals for HCV with a mechanism unrelated to known antiviral drugs and (2) a chemical tool to investigate the HCV life cycle, and particularly the dynamics of the HCV replicase complex, using fluorescent protein tags to visualize replicase complexes in living cells. Inhibition of PI4K, which is a host enzyme, may be associated with higher barriers to development of resistance than is inhibition of viral enzymes. The hepatitis C virus (HCV), which causes liver cancer, liver failure, and thousands of deaths per year, depends on an enzyme called PI4K in the cells it infects. We will investigate a class of chemical compounds that can block PI4K to determine whether they could lead to a new class of drugs against HCV. We will also use these compounds to investigate how HCV makes copies of itself and how this process depends on the activity of PI4K.