Discovery of Selective Small Molecule Type III Phosphatidylinositol 4-Kinase Alpha (PI4KIIIα) Inhibitors as Anti Hepatitis C (HCV) Agents

Citations Over TimeTop 10% of 2013 papers

Abstract

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 28 that displays high selectivity for PI4KIIIα and potently inhibits HCV replication in vitro.

Related Papers

• → Adenosylhomocysteinase like 1 interacts with nonstructural 5A and regulates hepatitis C virus propagation(2020)14 cited
• → Effects of resistance‐associated variants in genotype 2 hepatitis C virus on viral replication and susceptibility to antihepatitis C virus drugs(2019)10 cited
• → Identification of drug resistance and immune-driven variations in hepatitis C virus (HCV) NS3/4A, NS5A and NS5B regions reveals a new approach toward personalized medicine(2016)7 cited
• → Structure-activity relationships of fluorene compounds inhibiting HCV variants(2019)4 cited
• → Interferon sensitivity-determining region of hepatitis C virus influences virus production and interferon signaling(2017)4 cited