| First Author | Vaillancourt FH | Year | 2012 |
| Journal | J Virol | Volume | 86 |
| Issue | 21 | Pages | 11595-607 |
| PubMed ID | 22896614 | Mgi Jnum | J:188779 |
| Mgi Id | MGI:5442224 | Doi | 10.1128/JVI.01320-12 |
| Citation | Vaillancourt FH, et al. (2012) Evaluation of Phosphatidylinositol-4-Kinase IIIalpha as a Hepatitis C Virus Drug Target. J Virol 86(21):11595-607 |
| abstractText | Phosphatidylinositol-4-kinase IIIalpha (PI4KIIIalpha) is an essential host cell factor for hepatitis C virus (HCV) replication. An N-terminally truncated 130-kDa form was used to reconstitute an in vitro biochemical lipid kinase assay that was optimized for small-molecule compound screening and identified potent and specific inhibitors. Cell culture studies with PI4KIIIalpha inhibitors demonstrated that the kinase activity was essential for HCV RNA replication. Two PI4KIIIalpha inhibitors were used to select cell lines harboring HCV replicon mutants with a 20-fold loss in sensitivity to the compounds. Reverse genetic mapping isolated an NS4B-NS5A segment that rescued HCV RNA replication in PIK4IIIalpha-deficient cells. HCV RNA replication occurs on specialized membranous webs, and this study with PIK4IIIalpha inhibitor-resistant mutants provides a genetic link between NS4B/NS5A functions and PI4-phosphate lipid metabolism. A comprehensive assessment of PI4KIIIalpha as a drug target included its evaluation for pharmacologic intervention in vivo through conditional transgenic murine lines that mimic target-specific inhibition in adult mice. Homozygotes that induce a knockout of the kinase domain or knock in a single amino acid substitution, kinase-defective PI4KIIIalpha, displayed a lethal phenotype with a fairly widespread mucosal epithelial degeneration of the gastrointestinal tract. This essential host physiologic role raises doubt about the pursuit of PI4KIIIalpha inhibitors for treatment of chronic HCV infection. |
