1 research outputs found
Discovery of Selective Small Molecule Type III Phosphatidylinositol 4‑Kinase Alpha (PI4KIIIα) 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 PI4KIIIα is an essential component of these
replication organelles. RNA interference of PI4KIIIα results
in a breakdown of this replication complex and cessation of HCV replication
in Huh-7 cells. PI4KIIIα is a lipid kinase that interacts with
the HCV nonstructural 5A 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. We investigated if small molecule inhibitors of PI4KIIIα
could inhibit HCV replication in vitro. The synthesis and structure–activity
relationships associated with the biological inhibition of PI4KIIIα
and HCV replication are described. These efforts led directly to identification
of quinazolinone <b>28</b> that displays high selectivity for
PI4KIIIα and potently inhibits HCV replication in vitro