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

The Influenza A virus RNA-dependent RNA polymerase (RdRp) complex is a heterotrimeric enzyme essential for the replication and transcription of the viral genome. It is composed of three subunits: polymerase acidic (PA), polymerase basic 1 (PB1), and polymerase basic 2 (PB2). The complex operates via a unique 'cap-snatching' mechanism where the PB2 subunit binds to the 5'-cap of host pre-mRNAs, which are then cleaved by the PA endonuclease domain to serve as primers for viral mRNA synthesis catalyzed by the PB1 subunit. Because it is highly conserved across different influenza A strains and lacks a human homolog, it is a high-priority target for antiviral therapy. Current drugs targeting this complex include baloxavir marboxil (PA inhibitor), favipiravir (PB1 inhibitor), and the investigational drug pimodivir (PB2 inhibitor). However, the clinical utility of these agents is often limited by the rapid development of resistance mutations and the necessity for early treatment initiation.

Other names

Influenza A virus polymerase complexPA-PB1-PB2 complex3P complexInfluenza A virus RNA polymerase

The complex is targeted by three main classes of inhibitors: PA endonuclease inhibitors (e.g., baloxavir marboxil) which prevent 'cap-snatching' by blocking the cleavage of host pre-mRNA; PB1 inhibitors (e.g., favipiravir) which act as nucleoside analogs to cause chain termination or lethal mutagenesis; and PB2 inhibitors (e.g., pimodivir) which block the cap-binding domain to prevent the initiation of viral transcription.