title: Phosphatidylinositol 4-kinase III beta is the target of oxoglaucine and pachypodol (Ro 09-0179) for their anti-poliovirus activities, and is located at upstream of the target step of brefeldin A.
abstract: In recent years, phosphatidylinositol 4-kinase III beta (PI4KB) has emerged as a conserved target of anti-picornavirus compounds. In the present study, PI4KB was identified as the direct target of the plant-derived anti-picornavirus compounds, oxoglaucine and pachypodol (also known as Ro 09-0179). PI4KB was also identified as the target via which pachypodol interferes with brefeldin A (BFA)-induced Golgi disassembly in non-infected cells. Oxysterol-binding protein (OSBP) inhibitor also has interfering activity against BFA. It seems that this interference is not essential for the anti-poliovirus (PV) activities of BFA and PI4KB/OSBP inhibitors. BFA inhibited early to late phase PV replication (0 to 6 hr postinfection) as well as PI4KB inhibitor, but with some delay compared to guanidine hydrochloride treatment. In contrast with PI4KB/OSBP inhibitors, BFA inhibited viral nascent RNA synthesis, suggesting that BFA targets some step of viral RNA synthesis located downstream of the PI4KB/OSBP pathway in PV replication. Our results suggest that PI4KB is a major target of anti-picornavirus compounds identified in vitro for their anti-picornavirus activities and for some uncharacterized biological phenomena caused by these compounds, and that BFA and PI4KB/OSBP inhibitors synergistically repress PV replication by targeting distinct steps in viral RNA replication.
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama-shi, Tokyo 208-0011.
authors.forename: Minetaro
authors.initials: M
authors.lastname: Arita
authors.affiliation: Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Academician Georgi Bonchev Street, Bl.9-1113.
authors.forename: Stefan
authors.initials: S
authors.lastname: Philipov
authors.affiliation: Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 26 Academician Georgi Bonchev Street, BG-1113, Sofia, Bulgaria.
authors.forename: Angel S
authors.initials: AS
authors.lastname: Galabov
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020126:Brefeldin A / Q000378:metabolism; D006801:Humans; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D017955:Poliovirus / Q000502:physiology*; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D001058:Apomorphine; D020126:Brefeldin A; D017853:Phosphotransferases (Alcohol Group Acceptor); D011794:Quercetin; C008751:pachypodol; C111587:oxoglaucine; C581087:PI4KB protein, human
keywords: oxoglaucine; pachypodol (Ro 09-0179); phosphatidylinositol 4-kinase III beta; poliovirus