title: Phosphatidylinositol 4-kinase III beta is a target of enviroxime-like compounds for antipoliovirus activity.
abstract: Enviroxime is an antienterovirus compound that targets viral protein 3A and/or 3AB and suppresses a step in enterovirus replication by unknown mechanism. To date, four antienterovirus compounds, i.e., GW5074, Flt3 inhibitor II, TTP-8307, and AN-12-H5, are known to have similar mutations in the 3A protein-encoding region causing resistance to enviroxime (a G5318A [3A-Ala70Thr] mutation in poliovirus [PV]) and are considered enviroxime-like compounds. Recently, antienterovirus activity of a phosphatidylinositol 4-kinase III beta (PI4KB) inhibitor, PIK93, was reported, suggesting that PI4KB is an important host factor targetable by antienterovirus compounds (N. Y. Hsu et al., Cell 141:799-811, 2010). In this study, we analyzed the inhibitory effects of previously identified enviroxime-like compounds (GW5074 and AN-12-H5) and a newly identified antienterovirus compound, T-00127-HEV1, on phosphoinositide (PI) kinases. We found that T-00127-HEV1 inhibited PI4KB activity with a higher specificity for than other PI kinases, in contrast to GW5074, which had a broad specificity for PI kinases. In contrast, AN-12-H5 showed no inhibitory effect on PI4KB activity and only moderate inhibitory effects on PI 3-kinase activity. Small interfering RNA (siRNA) screening targeting PI kinases identified PI4KB is a target of GW5074 and T-00127-HEV1, but not of AN-12-H5, for anti-PV activity. Interestingly, T-00127-HEV1 and GW5074 did not inhibit hepatitis C virus (HCV) replication, in contrast to a strong inhibitory effect of AN-12-H5. These results suggested that PI4KB is an enterovirus-specific host factor required for the replication process and targeted by some enviroxime-like compounds (T-00127-HEV1 and GW5074) and that enviroxime-like compounds may have targets other than PI kinases for their antiviral effect.
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, 4-7-1 Gakuen, Tokyo 208-0011, Japan. minetaro@nih.go.jp
authors.forename: Minetaro
authors.initials: M
authors.lastname: Arita
authors.forename: Hirotatsu
authors.initials: H
authors.lastname: Kojima
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nagano
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Okabe
authors.forename: Takaji
authors.initials: T
authors.lastname: Wakita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimizu
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000998:Antiviral Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D004770:Enterovirus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D010091:Oximes; D010636:Phenols / Q000494:pharmacology; D011051:Poliomyelitis / Q000188:drug therapy / Q000821:virology*; D017955:Poliovirus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D013045:Species Specificity; D013449:Sulfonamides; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D007211:Indoles; D010091:Oximes; D010636:Phenols; D013449:Sulfonamides; D014764:Viral Proteins; D019870:1-Phosphatidylinositol 4-Kinase; C021595:viroxime; C489251:5-iodo-3-((3,5-dibromo-4-hydroxyphenyl)methylene)-2-indolinone