Discovery of Selective Small Molecule Type III Phosphatidylinositol 4-Kinase Alpha (P14KIIIα) Inhibitors as Anti Hepatitis C (HCV) Agents

Hepatitis C virus (HCV) assembles many host cellular proteins into unique membranous replication structures as a prerequisite for viral replication, and PI4KIII alpha is an essential component of these replication organelles. RNA interference of PI4KIII alpha results in a breakdown of this replication complex and cessation of HCV replication in Huh-7 cells. PI4KIII alpha is a lipid kinase that interacts with the HCV nonstructural SA protein (NS5A) and enriches the HCV replication complex with its product, phosphoinositol 4-phosphate (PI4P). Elevated levels of PI4P at the endoplasmic reticulum have been linked to HCV infection in the liver of HCV infected patients.(1) We investigated if small molecule inhibitors of PI4KIII alpha could inhibit HCV replication in vitro. The synthesis and structure activity relationships associated with the biological inhibition of PI4KIII alpha and HCV replication are described. These efforts quinazolinone 28 that displays high selectivity for PI4KIII alpha and potently inhibits HCV replication in vitro. led directly to identification of quinazolinone 28 that displays high selectivity for PI4KIII alpha and potently inhibits HCV replication in vitro.