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 28 that displays high selectivity for PI4KIIIα and potently inhibits HCV replication in vitro.
Infectious Diseases Medicines Discovery Unit, GlaxoSmithKline , 5 Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States.
Anna L
AL
Leivers
Matthew
M
Tallant
J Brad
JB
Shotwell
Scott
S
Dickerson
Martin R
MR
Leivers
Octerloney B
OB
McDonald
Jeff
J
Gobel
Katrina L
KL
Creech
Susan L
SL
Strum
Amanda
A
Mathis
Sabrinia
S
Rogers
Chris B
CB
Moore
Janos
J
Botyanszki
D019870:1-Phosphatidylinositol 4-Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051381:Rats; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D019870:1-Phosphatidylinositol 4-Kinase