Influenza A virus RNA-directed RNA polymerase complex (RdRp) (RdRp)

The Influenza A virus RNA-directed RNA polymerase (RdRp) complex is a heterotrimeric enzyme essential for the viral life cycle, consisting of the PA, PB1, and PB2 subunits (UniProt: P03433, P03431, P03428). It resides in the host cell nucleus where it orchestrates both the replication of the viral RNA genome and the transcription of viral mRNA (PubMed: 25471880). A defining feature of this complex is its "cap-snatching" activity: the PB2 subunit binds to the 5' caps of host pre-mRNAs, which are then cleaved by the PA subunit's endonuclease domain to serve as primers for viral transcription (Nature: 10.1038/nature13545). This mechanism is unique to the virus and lacks a human counterpart, making the RdRp an ideal target for highly specific antiviral agents. Current clinical strategies include the use of Baloxavir marboxil to inhibit the PA endonuclease and Favipiravir to target the PB1 catalytic site (StatPearls: NBK541063). However, the rapid emergence of resistance mutations, such as the I38T substitution in PA, remains a significant therapeutic challenge in the management of influenza infections (PubMed: 30416046).

Other names

Influenza A virus RNA polymeraseFluA RdRpPA-PB1-PB2 complexHeterotrimeric RNA polymerase

Inhibition of the PA subunit endonuclease activity to prevent cap-snatching (StatPearls: NBK541063), inhibition of the PB2 subunit cap-binding site (PubMed: 28111432), or acting as a nucleoside analogue to cause chain termination via the PB1 subunit (PubChem: CID 492405).