Molecular Pathogenesis of Neural Lesions Induced by Poliovirus Type 1

Kojima

Nagano

et al. 2013

103

121

Enviroxime is an antipicornavirus compound that targets host phosphatidylinositol 4-kinase III beta (PI4KB) activity for its antipicornavirus activity. To date, several antipoliovirus (PV) compounds similar to enviroxime that are associated with a common resistance mutation in viral protein 3A (a G5318A [3A-Ala70Thr] mutation in PV) have been identified. Most of these compounds have a direct inhibitory effect on PI4KB activity, as well as enviroxime (designated major enviroxime-like compounds). However, one of the compounds, AN-12-H5, showed no inhibitory effect on PI4KB and was considered to belong to another group of enviroxime-like compounds (designated minor enviroxime-like compounds). In the present study, we performed a small interfering RNA (

mentioning

confidence: 99%

Oxysterol-Binding Protein Family I Is the Target of Minor Enviroxime-Like Compounds

Kojima

Nagano

et al. 2013

103

121

“…PV is the causative agent of poliomyelitis, which is caused by the destruction of motor neurons by direct infection by PV in the cells (12,19). With the established live attenuated oral PV vaccine (OPV) and inactivated PV vaccine (IPV) for PV (43,44), the global eradication program for poliomyelitis has been continued by the Global Polio Eradication Initiative (GPEI) of the World Health Organization (WHO) since 1988.…”

mentioning

confidence: 99%

Phosphatidylinositol 4-Kinase III Beta Is a Target of Enviroxime-Like Compounds for Antipoliovirus Activity

Kojima

Nagano

et al. 2011

142

195

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.

“…P oliovirus (PV) is a small nonenveloped virus with a singlestrand positive genomic RNA of about 7,500 nucleotides (nt) belonging to Human enterovirus C in the genus Enterovirus, the family Picornaviridae. PV is the causative agent of poliomyelitis, which is caused by the destruction of motor neurons by the direct infection of PV in the cells (17,26). With established live attenuated oral PV vaccine (OPV) and inactivated PV vaccine (IPV) for PV (72,73), the global eradication program for poliomyelitis has been continued by the Global Polio Eradication Initiative (GPEI) of the World Health Organization (WHO) since 1988.…”

mentioning

confidence: 99%

Valosin-Containing Protein (VCP/p97) Is Required for Poliovirus Replication and Is Involved in Cellular Protein Secretion Pathway in Poliovirus Infection

Wakita

Shimizu

2012

Poliovirus (PV) modifies membrane-trafficking machinery in host cells for its viral RNA replication. To date, ARF1, ACBD3, BIG1/BIG2, GBF1, RTN3, and PI4KB have been identified as host factors of enterovirus (EV), including PV, involved in membrane traffic. In this study, we performed small interfering RNA (siRNA) screening targeting membrane-trafficking genes for host factors required for PV replication. We identified valosin-containing protein (VCP/p97) as a host factor of PV replication required after viral protein synthesis, and its ATPase activity was essential for PV replication. VCP colocalized with viral proteins 2BC/2C and 3AB/3B in PV-infected cells and showed an interaction with 2BC and 3AB but not with 2C and 3A. Knockdown of VCP did not suppress the replication of coxsackievirus B3 or Aichi virus. A VCP-knockdown-resistant PV mutant had an A4881G (a mutation of E253G in 2C) mutation, which is known as a determinant of a secretion inhibition-negative phenotype. However, knockdown of VCP did not affect the inhibition of cellular protein secretion caused by overexpression of each individual viral protein. These results suggested that VCP is a host factor required for viral RNA replication of PV among membrane-trafficking proteins and provides a novel link between cellular protein secretion and viral RNA replication.