Influenza virus RNA-dependent RNA polymerase complex (RdRp) (RdRp)

The influenza virus RNA-dependent RNA polymerase (RdRp) complex is a heterotrimeric enzyme essential for the life cycle of influenza A and B viruses. It consists of three subunits: polymerase acidic (PA), polymerase basic 1 (PB1), and polymerase basic 2 (PB2) (UniProt: P03433, P03431, P03428). The complex resides in the host cell nucleus where it performs two distinct functions: transcription of viral mRNAs and replication of the viral RNA (vRNA) genome (PubMed: 25344324). A critical step in transcription is cap-snatching, where the PB2 subunit binds host pre-mRNA 5' caps and the PA subunit's endonuclease domain cleaves the RNA to create a primer for viral synthesis (Nature: 10.1038/nature14020). As a therapeutic target, the RdRp is highly attractive because it is highly conserved across influenza strains and lacks a human homolog. Current drugs like Baloxavir marboxil specifically inhibit the PA endonuclease activity, while Favipiravir acts as a prodrug that, once phosphorylated, inhibits the PB1 catalytic subunit (StatPearls: NBK541071).

Other names

PA-PB1-PB2 complexInfluenza RNA polymeraseFlu RdRpInfluenza virus polymerase complexHeterotrimeric RNA polymerase

The complex is targeted via multiple distinct mechanisms: Baloxavir marboxil inhibits the PA subunit's cap-dependent endonuclease activity; Pimodivir inhibits the PB2 subunit's cap-binding site; and Favipiravir acts as a nucleoside analogue that is incorporated into the nascent RNA strand by the PB1 subunit, leading to chain termination or lethal mutagenesis (PubMed: 30334588, 24733883).