Destabilization of PDK1 by Hsp90 inactivation suppresses hepatitis C virus replication through inhibition of PRK2-mediated viral RNA polymerase phosphorylation

► Hsp90 inhibition destabilized PDK1 in Huh7 cells through the proteosome pathway. ► Destabilization of PDK1 led to decrease in the abundance of active form PRK2 level. ► Hsp90 inhibitor 17-DMAG abrogated PRK2-mediated HCV NS5B phosphorylation. ► Combination of 17-DMAG and a PRK2 inhibitor effectively suppressed HCV replication.