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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 antipicornavirus 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.Key words oxoglaucine, pachypodol (Ro 09-0179), phosphatidylinositol 4-kinase III beta, poliovirus.In a previous study, we tested a series of aporphinoid alkaloids isolated from Glaucium flavum Crantz (yellow horn poppy) (1) or obtained synthetically (2) in vitro for their antiviral activities against viruses belonging to several taxonomic groups, including picorna-, orthomyxo-, paramyxo-and herpesviruses. We found that one of these compounds, oxoglaucine, had a wellpronounced inhibitory effect on the replication of PV type 1 (Mahoney) from the Enterovirus genus in the Picornaviridae family (3).