Influenza virus RNA-directed RNA polymerase (RdRp)

The Influenza virus RNA-directed RNA polymerase (RdRp) is a heterotrimeric enzyme complex essential for the viral life cycle, composed of the Polymerase Acidic (PA), Polymerase Basic 1 (PB1), and Polymerase Basic 2 (PB2) subunits (UniProt: P03433, P03431, P03428). It resides within the viral ribonucleoprotein (vRNP) complex and is responsible for both replicating the viral RNA genome and transcribing viral mRNAs. A distinctive feature of this target is its 'cap-snatching' mechanism, in which the PB2 subunit binds to host cellular pre-mRNAs and the PA subunit cleaves them to generate primers for viral protein synthesis (PubMed: 25119035). Because humans lack a direct ortholog of this viral polymerase, it serves as a highly specific target for antiviral drug development with a favorable therapeutic index. In clinical practice, this target is addressed by several classes of inhibitors. Baloxavir marboxil is a first-in-class small molecule that targets the PA endonuclease domain, effectively halting the initiation of viral transcription (NEJM: 10.1056/NEJMoa1716197). Alternatively, nucleoside analogs like Favipiravir are phosphorylated by host enzymes into active forms that are recognized by the PB1 subunit, leading to chain termination or a catastrophic accumulation of mutations in the viral genome (PNAS: 10.1073/pnas.1319731111). Despite the efficacy of these treatments, the high error rate of the RdRp itself facilitates the emergence of resistance mutations, such as the I38T substitution in the PA subunit, which poses a significant challenge for long-term clinical utility and pandemic preparedness.

Other names

Influenza virus RNA-dependent RNA polymeraseInfluenza polymerase complex3P complexPA-PB1-PB2 complexRNA-directed RNA polymerase

Inhibition of the cap-dependent endonuclease activity within the PA subunit to block viral mRNA transcription; incorporation into the nascent RNA strand by the PB1 subunit leading to chain termination or lethal mutagenesis; and interference with the PB2 subunit to prevent host cap binding (PubMed: 30183155, Nature: 10.1038/nature13545).