An Investigation of the Mechanism for a Novel Influenza Inhibitor Designed to Target the Import of PB1

Abstract

A novel inhibitor of PB1 import, referred to here as GM30, previously displayed nuclear retention of viral nucleoprotein (NP), which spurred the question of whether the compound directly or indirectly blocked viral ribonucleoprotein (vRNP) complex export. vRNPs are exported from the nucleus via exportin 1 (XPO1). Using verdinexor (VNXR), a direct inhibitor of vRNP export that binds to XPO1 and also blocks nuclear factor kappa B (NF-{kappa}B) export, we found that GM30 does not block nuclear export of NF-{kappa}B. GM30 likewise demonstrated high nuclear retention of NP but not as much as the direct inhibition of nuclear export by VNXR. When the compound was added hours after infection, the compound lost its ability to block nuclear export but VNXR retained its ability to block nuclear export. GM30 is therefore likely an indirect inhibitor of nuclear export because it disrupts the vRNP complex formation and impedes export from the nucleus by reducing nuclear import of PB1.